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Neurotrophins and the immune system
Abstract
The neurotrophins are a family of polypeptide growth factors that are essential for the development and maintenance of the vertebrate nervous system. In recent years, data have emerged indicating that neurotrophins could have a broader role than their name might suggest. In particular, the putative role of NGF and its receptor TrkA in immune system homeostasis has become a much studied topic, whereas information on the other neurotrophins is scarce in this regard. This paper reviews what is known about the expression and possible functions of neurotrophins and their receptors in different immune tissues and cells, as well as recent data obtained from studies of transgenic mice in our laboratory. Results from studies to date support the idea that neurotrophins may regulate some immune functions. They also play an important role in the development of the thymus and in the survival of thymocytes.
... In addition, autocrine and paracrine signaling by neurotrophins (NTs) has been implicated in glaucoma disease progression, especially through the loss of such nutrient and growth factor transport through the damaged LC region of the ONH [39,[140][141][142]. NTs are a family of nerve-growth factors including nerve growth factor (NGF), brainderived growth factor (BDNF), glial-derived neurotrophic factor (GDNF), neurotrophin 3 (NT-3), and neurotrophin 4/5 (NT-4/5) [140]. ...
... In addition, autocrine and paracrine signaling by neurotrophins (NTs) has been implicated in glaucoma disease progression, especially through the loss of such nutrient and growth factor transport through the damaged LC region of the ONH [39,[140][141][142]. NTs are a family of nerve-growth factors including nerve growth factor (NGF), brainderived growth factor (BDNF), glial-derived neurotrophic factor (GDNF), neurotrophin 3 (NT-3), and neurotrophin 4/5 (NT-4/5) [140]. NTs bind to protein tyrosine kinase (Trk) receptors and are highly involved in the peripheral [140] and central nervous immune responses [143]. ...
... NTs are a family of nerve-growth factors including nerve growth factor (NGF), brainderived growth factor (BDNF), glial-derived neurotrophic factor (GDNF), neurotrophin 3 (NT-3), and neurotrophin 4/5 (NT-4/5) [140]. NTs bind to protein tyrosine kinase (Trk) receptors and are highly involved in the peripheral [140] and central nervous immune responses [143]. In the healthy ONH, LC cells and astrocytes produce moderate levels of NTs, and microglia produce negligible levels [130,144]. ...
Glaucoma is a progressive disease and the leading cause of irreversible blindness. The limited therapeutics available are only able to manage the common risk factor of glaucoma, elevated intraocular pressure (IOP), indicating a great need for understanding the cellular mechanisms behind optic nerve head (ONH) damage during disease progression. Here we review the known inflammatory and fibrotic changes occurring in the ONH. In addition, we describe a novel mechanism of toll-like receptor 4 (TLR4) and transforming growth factor beta-2 (TGFβ2) signaling crosstalk in the cells of the ONH that contribute to glaucomatous damage. Understanding molecular signaling within and between the cells of the ONH can help identify new drug targets and therapeutics.
... However, other cell types, including immune system cells, can produce NTs and express their receptors on the cell surface [7][8][9]. These proteins also play a vital role in regulating immune functions [10][11][12], promoting the survival of different immune cells such as monocytes and lymphocytes and influencing cytokine expression [5,10,13]. ...
... However, other cell types, including immune system cells, can produce NTs and express their receptors on the cell surface [7][8][9]. These proteins also play a vital role in regulating immune functions [10][11][12], promoting the survival of different immune cells such as monocytes and lymphocytes and influencing cytokine expression [5,10,13]. ...
... Two different types of NTs receptors can be found within the CNS cells [14,27]. The Tropomyosin receptor kinase (Trk) binds preferentially to specific NTs to develop different functions in CNS, creating a high-affinity attachment [10,20,28]. These receptors include TrkA, TrkB, and TrkC, where TrkA binds to NGF, TrkB with BDNF and NT-4/5, and TrkC binds to NT-3 ( Figure 1) [14,29,30]. ...
Neurotrophins, such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin 3 (NT-3), NT-4, and NT-5, are proteins involved in several important functions of the central nervous system. The activation of the signaling pathways of these neurotrophins, or even by their immature form, pro-neurotrophins, starts with their recognition by cellular receptors, such as tropomyosin receptor kinase (Trk) and 75 kD NT receptors (p75NTR). The Trk receptor is considered to have a high affinity for attachment to specific neurotrophins, while the p75NTR receptor has less affinity for attachment with neurotrophins. The correct functioning of these signaling pathways contributes to proper brain development, neuronal survival, and synaptic plasticity. Unbalanced levels of neurotrophins and pro-neurotrophins have been associated with neurological disorders, illustrating the importance of these molecules in the central nervous system. Furthermore, reports have indicated that viruses can alter the normal levels of neurotrophins by interfering with their signaling pathways. This work discusses the importance of neurotrophins in the central nervous system, their signaling pathways, and how viruses can affect them.
... Neurotrophins are small molecules of polypeptides which bind to tyrosine kinase receptors and regulate various cellular processes including calcium homeostasis and also, inhibit free radical formation by increasing the levels of antioxidant enzymes [9]. Prominent examples of neurotrophins include brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4) [10]. BDNF is associated with depression, while other neurotrophins are linked to mood disorders [11]. ...
In 2008, the World Health Organization (WHO) stressed major depressive disorder (MDD) as the third most important cause of disease burden worldwide. Based on their projections, it is expected that by 2030, MDD will take the lead among the rest of the world’s health concerns. Brain derived neurotrophic factor 4 (BDNF4), a protein of neurotrophins family play pivotal role in maintaining neural plasticity, and its reduced level in the hippocampus and plasma have been reported in patients with MDD. Nootropic drugs serve as therapeutic interventions in mitigating MDD through diverse molecular mechanisms. Punica granatum (pomegranate) is acknowledged for its nutritional and medicinal properties, currently under medical scrutiny for its potential as a natural antidepressant. Various computational methodologies, including molecular docking, pharmacokinetics, ADME (absorption, distribution, metabolism and excretion) profile assessment, toxicological analysis, and prediction of biological activity, were employed to identify promising compounds among the phytochemicals present in Punica extract, focusing on their potential BDNF4-stimulating, nootropic, and antidepressant properties. The comprehensive examination of docking scores, interactions between proteins and ligands, pharmacological and toxicological attributes, along with the forecasting of biological activities, collectively underscores the potential attributes of M-Cymene, Flavylium, 2-(4-Methylphenyl)propan-2-ol, Thymol, and Pelletierine as prospective drug candidates targeting human BDNF4 for alleviating MDD.
... Melatonin powerfully regulates DC function, including suppressing the ROS and enhancing endogenous antioxidants [114], thereby preventing the suppressive effects of ROS on DC antigen-presenting capacity. As TrkB seems to have limited, if any, expression in human DCs [115], any increase in the extracellular NAS/melatonin ratio is likely to significantly impact on DC function via NAS/TrkB and how these cells drive the interactions of innate and adaptive immune systems. Cancer cell-derived kynurenine activation of the AhR, driving a decrease in melatonin will increase tolerogenic Tregs, whilst the loss of melatonin optimization of DC function contributes to suppressed activation of CD8+ t cells in the tumor microenvironment. ...
There is a growing interest in the role of alterations in mitochondrial metabolism in the pathoetiology and pathophysiology of cancers, including within the array of diverse cells that can form a given tumor microenvironment. The 'exhaustion' in natural killer cells and CD8+ t cells as well as the tolerogenic nature of dendritic cells in the tumor microenvironment seems determined by variations in mitochondrial function. Recent work has highlighted the important role played by the melatonergic pathway in optimizing mitochondrial function, limiting ROS production, endogenous antioxidants upregulation and consequent impacts of mitochondrial ROS on ROS-dependent microR-NAs, thereby impacting on patterned gene expression. Within the tumor microenvironment, the tumor, in a quest for survival, seeks to 'dominate' the dynamic intercellular interactions by limiting the capacity of cells to optimally function, via the regulation of their mitochondrial melatonergic pathway. One aspect of this is the tumor's upregulation of kynurenine and the activation of the aryl hydrocarbon receptor, which acts to metabolize melatonin and increase the N-acetylserotonin/melatonin ratio, with effluxed N-acetylserotonin acting as a brain-derived neurotrophic factor (BDNF) mimic via its activation of the BDNF receptor, TrkB, thereby increasing the survival and proliferation of tumors and cancer stem-like cells. This article highlights how many of the known regulators of cells in the tumor microenvironment can be downstream of the mitochondrial melatonergic pathway regulation. Future research and treatment implications are indicated.
... At 36 dpi, the target genes of DEmiRNAs were enriched in the Neurotrophin signaling pathway, Long-term potentiation, Axon guidance and Protein processing in endoplasmic reticulum (Fig. 4c). Neurotrophins and their receptors in neurotrophin signaling pathway are widely expressed in the immune system [41]. Neurotrophins can regulate the functions of lymphocytes and eosinophils, and promote B cell maturation, while also acting on hematopoietic lineage cells to regulate their hematopoietic function [42]. ...
Background
Toxocara canis is distributed worldwide, posing a serious threat to both human and dog health; however, the pathogenesis of T. canis infection in dogs remains unclear. In this study, the changes in microRNA (miRNA) expression profiles in the bone marrow of Beagle dogs were investigated by RNA-seq and bioinformatics analysis.
Results
Thirty-nine differentially expressed (DE) miRNAs (DEmiRNAs) were identified in this study. Among these, four DEmiRNAs were identified at 24 h post-infection (hpi) and all were up-regulated; eight DEmiRNAs were identified with two up-regulated miRNAs and six down-regulated miRNAs at 96 hpi; 27 DEmiRNAs were identified with 13 up-regulated miRNAs and 14 down-regulated miRNAs at 36 days post-infection (dpi). Among these DEmiRNAs, cfa-miR-193b participates in the immune response by regulating the target gene cd22 at 24 hpi. The novel_328 could participate in the inflammatory and immune responses through regulating the target genes tgfb1 and tespa1 , enhancing the immune response of the host and inhibiting the infection of T. canis at 96 hpi. In addition, cfa-miR-331 and novel_129 were associated with immune response and self-protection mechanisms at 36 dpi. 20 pathways were significantly enriched by KEGG pathway analysis, most of which were related to inflammatory response, immune response and cell differentiation, such as Cell adhesion molecules (CAMs), ECM-receptor interaction and Focal adhesion.
Conclusions
These findings suggested that miRNAs of Beagle dog bone marrow play important roles in the pathogenesis of T. canis infection in dogs and provided useful resources to better understand the interaction between T. canis and the hosts.
... As a consequence of their immunomodulatory role, neurotrophins have been associated with many immunological tumors, especially Bcell malignancies including acute lymphoblastic leukemia, diffuse large B-cell lymphoma, Burkitt's lymphoma and multiple myeloma (Hillis et al., 2016;Vega et al., 2003;Dubanet et al., 2015;Bellanger et al., 2011). ...
Neurotrophins (NTs) as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) play multiple roles in different settings including neuronal development, function and survival in both the peripheral and the central nervous systems from early stages. This report aims to provide a summary and subsequent review of evidences on the role of NTs in rare and non-common pediatric human diseases associated with changes in neurodevelopment. A variety of diseases has been analyzed and many have been linked to NTs neurobiological effects, including chronic granulomatous disease, hereditary sensory and autonomic neuropathy, Duchenne muscular dystrophy, Bardet-Biedl syndrome, Angelman syndrome, fragile X syndrome, trisomy 16, Williams-Beuren syndrome, Prader-Willi syndrome, WAGR syndrome, fetal alcohol spectrum disorders, Down syndrome and Klinefelter Syndrome. NTs alterations have been associated with numerous pathologic manifestations including cognitive defects, behavioral abnormalities, epilepsy, obesity, tumorigenesis as well as muscle-skeletal, immunity, bowel, pain sensibility and cilia diseases. In this report, we discuss that further studies are needed to clear a possible therapeutic role of NTs in these still often uncurable diseases.
... Neurotrophins (NTs) among with the brain-derived neurotrophic factor (BDNF) are structurally and functionally related growth factors that are widely expressed in a variety of tissues including the immune system. 23 Moreover, NTs and their Trk (tropomyosin-related kinase) receptors are involved by autocrine and/or paracrine signaling pathways in cancer cell growth and dissemination. 24 Binding of BDNF to its high-affinity receptor TrkB triggers cell survival by activating several signaling pathways (PI3K/Akt, MAPK, and PLC-). ...
Le lymphome diffus à grandes cellules B (DLBCL) est un des lymphomes B non-Hodgkiniens le plus agressif et le plus fréquent chez l’adulte avec deux sous-groupes principaux (GCB et ABC) sur le plan biologique et clinique.Malgré les avancées thérapeutiques apportées par l’immunochimiothérapie R-CHOP (anti-CD20, rituximab, associé à la chimiothérapie CHOP), 30 à 40 % des patients échappent ou sont réfractaires au traitement. Des données récentes montrent que des petites vésicules extracellulaires, « small EVs » libérées par les cellules de DLBCL portent l'antigène CD20 jouant le rôle de « récepteur leurre » vis-à-vis de l'immunothérapie. L’objectif de cette thèse était d’étudier la production de ces « small EVs », dont font parti les exosomes, de façon comparative par les cellules de type GCB et ABC, ainsi que leur rôle dans l’échappement des cellules tumorales à la cytotoxicité du rituximab dépendante de l’activation du complément (CDC). Nous avons de plus poursuivi les travaux précédents de l’équipe sur le rôle de la voie de signalisation BDNF/TrkB dans ce processus. Dans ce contexte, nous avons analysé la production des « small EVs », et leur niveau d’expression du CD20, par les cellules traitées avec un agoniste de TrkB, le 7,8-DHF. Aucune différence significative de taille et de concentration de ces vésicules des lignées de type GCB et ABC n'a été observée. Le niveau de CD20 dans les « small EVs » était corrélé à l'expression du CD20 membranaire des cellules parentales, indépendamment du sous-type de DLBCL. De manière intéressante, une expression plus élevée du CD20 au sein de ces vésicules et de la concentration en « small EVs » ont été observées dans les cultures traitées au 7,8-DHF comparativement aux cultures contrôles. Nous avons montré in vitro et in vivo (xénogreffe de SUDHL4 chez des souris SCID) que l'association de « small EVs » autologues ou hétérologues au rituximab protégeait les cellules tumorales et les tumeurs de la cytotoxicité du rituximab. De plus, la protection était significativement améliorée lorsque les exosomes étaient produits par des cellules traitées au 7,8-DHF. Enfin, une étude préliminaire a été initiée sur la signification clinique des « smallEVs », dont les exosomes plasmatiques et leur niveau d’expression du CD20 chez des patients atteints de DLBCL comparativement à des volontaires sains (VS). Nous montrons pour la première fois dans le DLBCL une augmentation de leur concentration périphérique par rapport aux VS. L’ensemble des travaux confirment in vivo le rôle des « small EVs » dans l'échappement à l’immunothérapie des tumeurs de DLBCL, et mettent en évidence à travers la voie BDNF/TrkB l’influence de circuits de régulations sur ce processus. Finalement ils apportent des arguments sur l’utilisation potentielle des « small EVs », dont les exosomes, comme biomarqueurs non-invasifs de la charge tumorale et de l’expression de cibles thérapeutiques comme le CD20, dans le suivi de la maladie et l’orientation thérapeutique.
... NGF has a high affinity for TrkA, but its function is affected by p75NTR [159]. It has been found that TrkA and p75NTR are involved in cell proliferation, differentiation, and survival in bone marrow and lymphoid tissue [160]. Moreover, NGF can promote the differentiation and migration of vascular smooth muscle cells and endothelial cells, mobilize and activate endothelial progenitor cells, and promote neovascularization [161]. ...
Pulpal and periapical diseases are the most common dental diseases. The traditional treatment is root canal therapy, which achieves satisfactory therapeutic outcomes—especially for mature permanent teeth. Apexification, pulpotomy, and pulp revascularization are common techniques used for immature permanent teeth to accelerate the development of the root. However, there are obstacles to achieving functional pulp regeneration. Recently, two methods have been proposed based on tissue engineering: stem cell transplantation, and cell homing. One of the goals of functional pulp regeneration is to achieve innervation. Nerves play a vital role in dentin formation, nutrition, sensation, and defense in the pulp. Successful neural regeneration faces tough challenges in both animal studies and clinical trials. Investigation of the regeneration and repair of the nerves in the pulp has become a serious undertaking. In this review, we summarize the current understanding of the key stem cells, signaling molecules, and biomaterials that could promote neural regeneration as part of pulp regeneration. We also discuss the challenges in preclinical or clinical neural regeneration applications to guide deep research in the future.
... It should be noted that IL-10-deficient B cells still display neurotrophic function in an in vitro model of oxygen-glucose deprivation [65], suggesting alternative neurotrophic production. Although leukocytes have the capacity to produce various neurotrophins, B cells are the primary lymphocytic source of brain-derived neurotrophic factor (BDNF), a necessary neurotrophin/neurotrophic factor for neuronal function in both health and disease [90]. In fact, B cells require BDNF for proper development in the bone marrow, BDNF can induce a Ca 2+ influx into B cells [80], and BDNF protects mature B cells from stress-induced apoptosis [23]. ...
B cells, also known as B lymphocytes or lymphoid lineage cells, are a historically understudied cell population with regard to brain-related injuries and diseases. However, an increasing number of publications have begun to elucidate the different phenotypes and roles B cells can undertake during central nervous system (CNS) pathology, including following ischemic and hemorrhagic stroke. B cell phenotype is intrinsically linked to function following stroke, as they may be beneficial or detrimental depending on the subset, timing, and microenvironment. Factors such as age, sex, and presence of co-morbidity also influence the behavior of post-stroke B cells. The following review will briefly describe B cells from origination to senescence, explore B cell function by integrating decades of stroke research, differentiate between the known B cell subtypes and their respective activity, discuss some of the physiological influences on B cells as well as the influence of B cells on certain physiological functions, and highlight the differences between B cells in healthy and disease states with particular emphasis in the context of ischemic stroke.
... Neurotrophins might be another possible mediator between immune-related diseases and the central nervous system [16,17]. They are substances responsible for the development, growth, and overall functioning of neurons; however, they might also modulate neurotransmitter release at presynaptic terminals [18,19]. ...
Brain-derived neurotrophic factor (BDNF) is a neurotrophin regulating synaptic plasticity, neuronal excitability, and nociception. It seems to be one of the key molecules in interactions between the central nervous system and immune-related diseases, i.e., diseases with an inflammatory background of unknown etiology, such as inflammatory bowel diseases or rheumatoid arthritis. Studies show that BDNF levels might change in the tissues and serum of patients during the course of these conditions, e.g., affecting cell survival and modulating pain severity and signaling pathways involving different neurotransmitters. Immune-related conditions often feature psychiatric comorbidities, such as sleep disorders (e.g., insomnia) and symptoms of depression/anxiety; BDNF may be related as well to them as it seems to exert an influence on sleep structure; studies also show that patients with psychiatric disorders have decreased BDNF levels, which increase after treatment. BDNF also has a vital role in nociception, particularly in chronic pain, hyperalgesia, and allodynia, participating in the formation of central hypersensitization. In this review, we summarize the current knowledge on BDNF’s function in immune-related diseases, sleep, and pain. We also discuss how BDNF is affected by treatment and what consequences these changes might have beyond the nervous system.
... BDNF exerts its physiological functions through two different types of receptors: Tyrosine kinase B (TrkB) with higher affinity and pan-neurotrophin receptor p75 (p75NTR) with lower affinity [76,77]. Outside the nervous system, neurotrophin receptors, including TrKB and P75 are expressed in tissues, such as skeletal muscle, bone, immune system cells (basophils, eosinophils, lymphocytes; macrophages; mast cells, neutrophils), cartilage, and synovium [77][78][79][80][81][82][83]. In this wide variety of tissues, neurotrophins play a constitutive role in regulating cell homeostasis and tissue development [77,80,82]. ...
Radiofrequency energy is a common treatment modality for chronic pain. While there are different forms of radiofrequency-based therapeutics, the common concept is the generation of an electromagnetic field in the applied area, that can result in neuromodulation (pulsed radiofrequency—PRF) or ablation. Our specific focus relates to PRF due to the possibility of modulation that is in accordance with the mechanisms of action of orthobiologics. The proposed mechanism of action of PRF pertaining to pain relief relies on a decrease in pro-inflammatory cytokines, an increase in cytosolic calcium concentration, a general effect on the immune system, and a reduction in the formation of free radical molecules. The primary known properties of orthobiologics constitute the release of growth factors, a stimulus for endogenous repair, analgesia, and improvement of the function of the injured area. In this review, we described the mechanism of action of both treatments and pertinent scientific references to the use of the combination of PRF and orthobiologics. Our hypothesis is a synergic effect with the combination of both techniques which could benefit patients and improve the life quality.
... Moreover, BDNF exerts anorexic actions at a CNS level by interacting with hypothalamic centers regulating appetite [109]. Interestingly, it has been demonstrated that, like other neurotrophins, BDNF contributes to the functioning of both innate and acquired immunity [110]. Such immunomodulatory property results in potential neuroprotective effects in the presence of neurodegenerative diseases [111]. ...
Metabolic Syndrome (MetS) is a cluster of metabolic alterations mostly related to visceral adiposity, which in turn promotes glucose intolerance and a chronic systemic inflammatory state, characterized by immune cell infiltration. Such immune system activation increases the risk of severe disease subsequent to viral infections. Strong correlations between elevated body mass index (BMI), type-2-diabetes and increased risk of hospitalization after pandemic influenza H1N1 infection have been described. Similarly, a correlation between elevated blood glucose level and SARS-CoV-2 infection severity and mortality has been described, indicating MetS as an important predictor of clinical outcomes in patients with COVID-19. Adipose secretome, including two of the most abundant and well-studied adipokines, leptin and interleukin-6, is involved in the regulation of energy metabolism and obesity-related low-grade inflammation. Similarly, skeletal muscle hormones-called myokines-released in response to physical exercise affect both metabolic homeostasis and immune system function. Of note, several circulating hormones originate from both adipose tissue and skeletal muscle and display different functions, depending on the metabolic context. This review aims to summarize recent data in the field of exercise immunology, investigating the acute and chronic effects of exercise on myokines release and immune system function.
... Furthermore, they regulate heterogeneous functions in some non-neuronal tissues, acting throughout specific transmembrane receptors with tyrosine kinase activity (Trk) [2,3]. Both NTS and their signaling receptors are evolutionarily conserved among vertebrates [4][5][6][7][8], including fish [9][10][11][12]. In particular, the gene encoding for BDNF in zebrafish is about 90% identical to its mammalian counterpart [13], and its respective protein was found in developing and adult fish [14,15]. ...
Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family and it is involved in several fundamental functions in the central and peripheral nervous systems, and in sensory organs. BDNF regulates the chemosensory systems of mammals and is consistently expressed in those organs. In zebrafish, the key role of BDNF in the biology of the hair cells of the inner ear and lateral line system has recently been demonstrated. However, only some information is available about its occurrence in the olfactory epithelium, taste buds, and cutaneous isolated chemosensory cells. Therefore, this study was undertaken to analyze the involvement of BDNF in the chemosensory organs of zebrafish during the larval and adult stages. To identify cells displaying BDNF, we compared the cellular pattern of BDNF-displaying cells with those immunoreactive for calretinin and S100 protein. Our results demonstrate the localization of BDNF in the sensory part of the olfactory epithelium, mainly in the ciliated olfactory sensory neurons in larvae and adult zebrafish. Intense immunoreaction for BDNF was also observed in the chemosensory cells of oral and cutaneous taste buds. Moreover, a subpopulation of olfactory sensory neurons and chemosensory cells of olfactory rosette and taste bud, respectively, showed marked immunopositivity for calcium-binding protein S100 and calretinin. These results demonstrate the possible role of BDNF in the development and maintenance of olfactory sensory neurons and sensory cells in the olfactory epithelium and taste organs of zebrafish during all stages of development.
... The biological basis of AN is poorly understood, although dysregulated immune pathways have been noted (Gibson and Mehler, 2019), together with aberrations in neurotrophins. Neurotrophins are growth factors pivotal for survival, development, and function of neurons but additionally play an important role in the immune system (Vega et al., 2003). Candidate gene-based research has demonstrated a link between neurotrophin genes, such as variants of the brain-derived neurotrophic factor (BDNF) gene, and AN Ribases et al., 2003;Rybakowski et al., 2007). ...
Brain-derived neurotrophic factor (BDNF) is a neuroprotective molecule known to be involved in neuroplasticity, learning and memory. Additionally, it may mitigate the effects of inflammation on the brain. There is inconclusive evidence as to whether reductions in BDNF found in AN are related to features associated with the illness such as changes in inflammatory markers and comorbidities, and whether they persist after recovery. This cross-sectional study measured BDNF and 36 inflammatory markers in the serum of individuals recovered from AN (rec-AN; n = 24), with acute AN (n = 56), and healthy controls (n = 51). We (a) compared BDNF concentrations between AN, rec-AN and controls including four pre-determined covariates; (b) assessed the relationship between BDNF and body mass index, eating disorder (ED) psychopathology and depression; and (c) correlated BDNF with inflammatory markers, stratified by group. The AN group showed reductions in BDNF compared to controls and rec-AN. BDNF was negatively associated with depression and ED psychopathology in the whole sample, but not the AN sample. BDNF was positively correlated with three inflammatory markers in the control group (interleukin (IL)-8, Eotaxin-3, tumor necrosis factor (TNF)-α) and negatively correlated with one (IL-16). The only pro-inflammatory marker associated with BDNF in the AN group was TNF-α, and no pro-inflammatory markers were associated with BDNF in the rec-AN group. These results indicate that BDNF serum concentrations may be a state marker of AN. In people with acute AN, BDNF levels seem to be linked to TNF-α signalling. However, BDNF concentrations do not appear to reflect AN symptom severity.
... Однако у части пациентов терапия не всегда оказывается эффективной, что может быть связано с участием в патогенезе этих заболеваний не только цитокинов, но и других биологически активных веществ. Считается, что вместе с цитокинами в развитии воспалительной реакции принимают участие нейропептиды и нейротрофины [6][7][8][9]. ...
Goal. To assess the expression of neurotrophin, a nerve growth factor, amphiregulin, an epidermal growth factor, semaphorin 3A, a nerve repulsion factor, and PGP9.5 protein, a nerve fiber marker, in the skin of patients suffering from atopic dermatitis and psoriasis. Materials and methods. The study involved 30 patients suffering from atopic dermatitis and 30 patients suffering from psoriasis vulgaris. The disease severity was assessed by SCORAD and PASI. The extent of itching was assessed by the visual analogue scale. The expression of amphiregulin, semaphorin 3A (a nerve growth factor) and PGP9.5 protein (a nerve fiber marker) in the skin of patients was assessed by the indirect immunofluorescence method. Quantitative parameters of their expression were assessed by using the basic pack of the Olympus Fluoview software, Ver. 1.7b. Results. Increased epidermal innervation was revealed in the patients suffering from atopic dermatitis and psoriasis, which demonstrates an increased skin production of anti-inflammatory neuropeptides and reduced itching sensitivity threshold. A positive correlation between the itching extent and skin expression of neurotrophin (a nerve growth factor) was revealed in the patients with atopic dermatitis. In patients with severe psoriasis, an increased skin expression of amphiregulin, an epidermal growth factor, was discovered. Conclusion. These data demonstrate a pathogenic value of neurotrophin, a nerve growth factor, for the development of itching in patients with atopic dermatitis and amphiregulin in case of psoriasis vulgaris.
... Until now it was unknown whether treatment with NT-3 affects immune cells of stroke patients. In addition to its functions in neuroplasticity, immunomodulatory functions of NT-3 are plausible because, depending on the activation state of the immune cells, neurotrophins and their receptors are expressed 16,17 . ...
Background and purpose
Stroke therapy still lacks successful measures to improve post stroke recovery. Neurotrophin-3 (NT-3) is one promising candidate which has proven therapeutic benefit in motor recovery in acute experimental stroke. Post stroke, the immune system has opposing pathophysiological roles: pro-inflammatory cascades and immune cell infiltration into the brain exacerbate cell death while the peripheral immune response has only limited capabilities to fight infections during the acute and subacute phase. With time, anti-inflammatory mechanisms are supposed to support recovery of the ischemic damage within the brain parenchyma. However, interestingly, NT-3 can improve recovery in chronic neurological injury when combined with the pro-inflammatory stimulus lipopolysaccharide (LPS).
Aim
We elucidated the impact of NT-3 on human monocyte and T cell activation as well as cytokine production ex vivo after stroke. In addition, we investigated the age-dependent availability of the high affinity NT-3 receptor TrkC upon LPS stimulation.
Methods
Peripheral blood mononuclear cells (PBMCs) were isolated from acute stroke patients and controls and incubated with different dosages of NT-3 (10 and 100 ng/ml) and with or without LPS or anti-CD3/CD28 for 48 h. Total TrkC expression and cell activation (CD25, CD69 and HLA-DR) were assessed by FACS staining. IFN-γ, TNF-α, IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, IL-17A, IL-17F, IL-21 and IL-22 were quantified by cytometric bead array.
Results
Most monocytes and only a small proportion of T cells expressed TrkC in blood from humans without stroke. Activation of cells from young humans (without strokes) using anti-CD3/CD28 or LPS partially reduced the proportion of monocytes expressing TrkC whilst they increased the proportion of T cells expressing TrkC. In contrast, activation of cells from elderly humans (without strokes) did not affect the proportion of monocytes expressing TrkC and only anti-CD3/CD28 led to an increase in the proportion of CD4+ T cells expressing TrkC.
In blood from stroke patients or controls, NT-3 treatment reduced the percentage of monocytes and CD4+ and CD8+ T cells that were activated and reduced all cytokines investigated besides IL-21.
Conclusions
NT-3 attenuated immune responses in cells from stroke patients and controls. The mechanism whereby human immune cells respond to NT-3 may be via TrkC receptors whose levels are regulated by stimulation. Further work is required to determine whether the induction of sensorimotor recovery in rodents by NT-3 after CNS injury is caused by this attenuation of the immune response.
... Likewise, IL-6 and TNF-α are able to enhance BDNF secretion from peripheral blood monocytes (29). Overall, peripheral blood BDNF has a complex regulatory network involving lymphocytes and anti-and pro-inflammatory cytokines and performs a broad spectrum of activities in non-neural tissues, apart from its regulatory role in inflammation and autoimmune demyelination in the CNS (33)(34)(35)(36)(37)(38). Based on these results, it is indicated that BDNF is a key factor in autoimmune and inflammatory diseases. ...
Numerous recent studies reported that brain-derived neurotrophic factor (BDNF) also exists in the peripheral blood to regulate the proliferation, differentiation and survival of lymphocytes. Besides the role of BDNF in neuron repair, circulatory BDNF also enhances the proliferation and reduces apoptosis of lymphocytes. Peripheral lymphocytes express both BDNF and its receptors. Increasing evidence has indicated that altered BDNF serum levels significantly affect patients with autoimmune inflammatory diseases and may also be linked to the pathogenesis of diseases. For instance, systemic lupus erythematosus, an autoimmune inflammatory disease involving multiple organs, is frequently linked to altered B lymphocyte function, imbalance of T-cell subpopulations and loss of immune tolerance, which dysregulates the immune regulatory network with excessive secretion of inflammatory cytokines. The present review summarized studies that suggest a potential link between circulatory BDNF and autoimmune inflammatory diseases.
... Specifically, NT-3 is crucial for neurite growth, differentiation, and neuronal survival, and also plays a role in early neurodevelopment, given that its levels increased in the fetal stage and decreased in adulthood [7,31]. Its receptor, TrkC, regulates different signaling pathways, such as extracellular signalregulated kinases (ERKs) and phosphatidylinositol-3-kinase (PI3K)-protein kinase B (AKT) pathways that promote cell growth, differentiation, and survival, and phospholipase C-γ (PLCγ) signaling that is critical for synaptic plasticity ( Figure 5) [32,33]. The neurotrophin hypothesis for schizophrenia claims that abnormal levels of these neurotrophic factors induce neurodevelopment and neuroplasticity disruptions [5,34]. ...
The neurobiology of schizophrenia is multifactorial, comprising the dysregulation of several biochemical pathways and molecules. This research proposes a peripheral biomarker for schizophrenia that involves the second extracellular loop of norepinephrine transporter (NEText), the tropomyosin receptor kinase C (TrkC), and the neurotrophin-3 (NT-3) in T cells. The study of NEText, NT-3, and TrkC was performed in T cells and plasma extracted from peripheral blood of 54 patients with schizophrenia and 54 healthy controls. Levels of NT-3, TrkC, and NET were significantly lower in plasma and T cells of patients compared to healthy controls. Co-immunoprecipitation (co-IPs) showed protein interactions with Co-IP NEText–NT-3 and Co-IP NEText–TrkC. Computational modelling of protein–peptide docking by CABS-dock provided a medium–high accuracy model for NT-3–NEText (4.6935 Å) and TrkC–NEText (2.1365 Å). In summary, immunocomplexes reached statistical relevance in the T cells of the control group contrary to the results obtained with schizophrenia. The reduced expression of NT-3, TrkC, and NET, and the lack of molecular complexes in T cells of patients with schizophrenia may lead to a peripheral dysregulation of intracellular signaling pathways and an abnormal reuptake of norepinephrine (NE) by NET. This peripheral molecular biomarker underlying schizophrenia reinforces the role of neurotrophins, and noradrenergic and immune systems in the pathophysiology of schizophrenia.
... In another work, BDNF knockout blocked the maturation of T cell precursors and caused subsequent reductions in T cell counts [52]. These findings are in line with previous works showing TRKB and p75NTR expression in thymocytes and stromal cells of the thymus, and the importance of BDNF/TRKB for thymocyte survival at different developmental stages [53,54]. BDNF can be found at high levels in the serum and plasma [55]. ...
Emerging studies have highlighted brain-derived neurotrophic factor (BDNF), a neuronal growth factor abundant in the peripheral blood, and its tyrosine kinase receptor TRKB, as onco-genes and proteins that support the survival of malignant hematological cells. In contrast, other researchers reported on a favorable association between BDNF blood levels and prognosis, chemotherapy response and neurological side effects in patients with hematological malignancies. Here, we review the accumulated data regarding the expression of BDNF and its receptors in normal hematopoietic and lymphatic cells and tissue. In addition, in-vitro experiments, animal models and human sample studies that investigated the role of BDNF and its receptors in hematological malignancies are discussed. Finally, directions for future research aimed at revealing the mechanisms underlying the protective effect of BDNF in patients with these diseases are suggested.
... b-NGF can interact with its high affinity receptor, TrkA, or a low affinity, p75 receptor (17) to exert its biological activity. These receptors are expressed in many lymphoid organs, and neurotrophins, including NGF, have multiple documented immunomodulatory roles affecting among others the proliferation, differentiation, activation and chemotaxis of mast cells, B-cells, T-cells, monocytes/macrophages and other immune system cells (18). Despite that, information on the function of NGF with respect to SS is still limited. ...
Introduction
The purpose of this study was to identify differentially expressed proteins in salivary glands of the ERdj5 knockout mouse model for Sjögren’s syndrome and to elucidate possible mechanisms for the morbid phenotype development. At the same time, we describe for the first time the sexual dimorphism of the murine submandibular salivary gland at the proteome level.
Methods
We performed Liquid Chromatography/Mass Spectrometry in salivary gland tissues from both sexes of ERdj5 knockout and 129SV wildtype mice. The resulting list of proteins was evaluated with bioinformatic analysis and selected proteins were validated by western blot and immunohistochemistry and further analyzed at the transcription level by qRT-PCR.
Results
We identified 88 deregulated proteins in females, and 55 in males in wildtype vs knockout comparisons. In both sexes, Kallikrein 1b22 was highly upregulated (fold change>25, ANOVA p<0.0001), while all other proteases of this family were either downregulated or not significantly affected by the genotype. Bioinformatic analysis revealed a possible connection with the downregulated NGF that was further validated by independent methods. Concurrently, we identified 416 proteins that were significantly different in the salivary gland proteome of wildtype female vs male mice and highlighted pathways that could be driving the strong female bias of the pathology.
Conclusion
Our research provides a list of novel targets and supports the involvement of an NGF-mediating proteolytic deregulation pathway as a focus point towards the better understanding of the underlying mechanism of Sjögren’s syndrome.
... [4] The Neurotrophin family includes the Nerve Growth Factor, Brain Derived neurotrophic Factor, NT-3, NT-4 and NT-6. [5,6] OPEN ACCESS https://scidoc.org/IJDOS.php [7] It plays a role in maintaining the phenotype and the survival of specific peripheral and central neurons during their phase of development and maturation. ...
... Although further research is needed, it can be concluded that the factors involved in the process of neurogenesis may serve as biomarkers of depressive disorders. It is worth mentioning that neurotrophins through their widespread expression also in immune cells are candidate molecules for regulating neuroimmune interactions [71]. ...
(1) Background: The neurogenic theory suggests that impaired neurogenesis within the dentate gyrus of the hippocampus is one of the factors causing depression. Immunology also has an impact on neurotrophic factors. The aim of the study was to assess the importance of selected genes involved in the process of neurogenesis i.e., nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF) and neuron-restrictive silencer factor (REST gene) in the etiopathogenesis of depressive disorders. (2) Methods: A total of 189 subjects took part in the study (95 depressed patients, 94 healthy controls). Sociodemographic data were collected. The severity of depressive symptoms was assessed using the Hamilton Depression Rating Scale (HDRS). RT-PCR was used to assess gene expression at the mRNA levels, while Enzyme-Linked Immunosorbent Assay (ELISA) was used to assess gene expression at the protein level. (3) Results: Expression of NGF, BDNF, REST genes is lower in depressed patients than in the control group, whereas the expression of GDNF gene is higher in patients with depressive disorders than in the group of healthy volunteers. (4) Conclusions: The expression of selected genes might serve as a biomarker of depression.
... Modulation of the immune response acutely after injury can halt the progressive secondary pathology resulting in reduced lesion sizes and improved functional outcome. There is modest evidence suggesting that NT3 can modulate the response of immune cells 116 . Whilst serum NT3 levels were not elevated chronically, see below, there is the chance that a minimal increase in NT3 occurred after treatment and this is sufficient to affect the immune response. ...
Traumatic spinal cord injury (SCI) in humans occurs most frequently in the cervical spine where it can cause substantial sensorimotor impairments to upper limb function. The altered input to spinal circuits below the lesion leads to maladaptive reorganisation which often leads to hyperreflexia in proprioceptive circuits. Neurotrophin 3 (NT3) is growth factor essential for the development of proprioceptive neurons. We have previously shown that following bilateral corticospinal tract axotomy, intramuscular delivery of an Adeno-Associated Viral vector encoding NT3 (AAV-NT3) induces proprioceptive circuit reorganisation linked to functional recovery. To assess its therapeutic effects following a clinically relevant bilateral C5-C6 contusion in rats, AAV-NT3 was injected intramuscularly into the dominant limb 24 hours after injury and forelimb function was assessed over 13 weeks. The injury generated hyperreflexia of a distal forelimb proprioceptive circuit. There was also loss of fine motor skills during reach-and-grasp and walking on a horizontal ladder. Ex vivo magnetic resonance imaging (MRI) revealed atrophy of the spinal cord and white matter disruption throughout the lesion site together with extensive loss of grey matter. Unexpectedly, animals treated with AAV-NT3 had a slightly smaller lesion in the regions close to the epicentre compared to PBS treated animals. Rats treated with AAV-NT3 showed subtly better performance on the horizontal ladder and transient benefits on reach-and-grasp. AAV-NT3 did not normalise hyperreflexia in a treated muscle. The treatment increased the amount of NT3 in treated muscles but, unexpectedly, serum levels were only elevated in a small subset of animals. These results show that this dose and delivery of AAV-NT3 may generate subtle improvements in locomotion but additional treatments will be required to overcome the widespread sensorimotor deficits caused by contusion injury.
... However, these two parameters were similar between the pSS and RA groups. Our study, therefore, suggests a different involvement of BDNF in pSS and RA physiopathology, either by its role in the nervous system (39), where BDNF is involved in proliferation and survival of nervous tissue (40) or by its action on the immune system (41) where BDNF affects the proliferation of T-and B-lymphocytes (42,43). I-TAC/CXCL11 is an IFNg-inducible chemokine, as are CXCL9 and CXCL10 (44), whose main function is to attract CXCR3-expressing cells (mainly activated T-lymphocytes, Natural Killer lymphocytes, and monocytes/macrophages) to the inflammatory site. ...
Context
Primary Sjögren’s syndrome (pSS) is a complex heterogeneous autoimmune disease (AID) which can mimic rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). Our exploratory study investigated serum biomarkers that may discriminate pSS from RA and SLE.
Methods
Serum concentrations of 63 biomarkers involved in immune cell trafficking, inflammatory response, cellular movement, and cell-to-cell signaling were measured in AID patients, included prospectively into the study at the Montpellier University Hospital. A multivariate analysis by multiple logistic regression was performed, and discriminative power assessed using logistic regression adjusted on significant demographic factors.
Results
Among the 95 patients enrolled, 42 suffered from pSS, 28 from RA, and 25 from SLE. Statistical analysis showed that concentrations of BDNF (OR = 0.493 with 95% CI [0.273–0.891]; p = 0.0193) and I-TAC/CXCL11 (OR = 1.344 with 95% CI [1.027–1.76]; p = 0.0314) can significantly discriminate pSS from RA. Similarly, greater concentrations of sCD163 (OR = 0.803 with 95% CI [0.649–0.994]; p = 0.0436), Fractalkine/CX3CL1 (OR = 0.534 with 95% CI [0.287–0. 991]; p = 0.0466), MCP-1/CCL2 (OR = 0.839 with 95% CI [0.732–0.962]; p = 0.0121), and TNFa (OR = 0.479 with 95% CI [0.247–0.928]; p = 0.0292) were associated with SLE diagnosis compared to pSS. In addition, the combination of low concentrations of BDNF and Fractalkine/CX3CL1 was highly specific for pSS (specificity 96.2%; positive predictive value 80%) compared to RA and SLE, as well as the combination of high concentrations of I-TAC/CXCL11 and low concentrations of sCD163 (specificity 98.1%; positive predictive value 75%).
Conclusion
Our study highlights biomarkers potentially involved in pSS, RA, and SLE pathophysiology that could be useful for developing a pSS-specific diagnostic tool.
... BDNF is part of a family of structurally related peptides, named neurotrophins, which are able to interact with two classes of receptors expressed on cell membrane surfaces, namely, tropomyosin receptor kinase (Trk) A-C, which binds to diverse neurotrophins, and the p75 neurotrophin receptor (p75NTR) (Chao, 2003). In general, both autocrine and paracrine mechanisms are used for the synthesis and action of neurotrophins by different cell types in the nervous, immune, and endocrine systems (Vega et al., 2003). The most important neurogenesis and neuroprotectant roles come from the BDNF activity over TrkB receptors (Ibáñez, 1995;Fossati et al., 2004). ...
Major depressive disorder (MDD) affects millions of people worldwide and is a leading cause of disability. Several theories have been proposed to explain its pathological mechanisms, and the “neurotrophin hypothesis of depression” involves one of the most relevant pathways. Brain-derived neurotrophic factor (BDNF) is an important neurotrophin, and it has been extensively investigated in both experimental models and clinical studies of MDD. Robust empirical findings have indicated an association between increased BDNF gene expression and peripheral concentration with improved neuronal plasticity and neurogenesis. Additionally, several studies have indicated the blunt expression of BDNF in carriers of the Val66Met gene polymorphism and lower blood BDNF (serum or plasma) levels in depressed individuals. Clinical trials have yielded mixed results with different treatment options, peripheral blood BDNF measurement techniques, and time of observation. Previous meta-analyses of MDD treatment have indicated that antidepressants and electroconvulsive therapy showed higher levels of blood BDNF after treatment but not with physical exercise, psychotherapy, or direct current stimulation. Moreover, the rapid-acting antidepressant ketamine has presented an early increase in blood BDNF concentration. Although evidence has pointed to increased levels of BDNF after antidepressant therapy, several factors, such as heterogeneous results, low sample size, publication bias, and different BDNF measurements (serum or plasma), pose a challenge in the interpretation of the relation between peripheral blood BDNF and MDD. These potential gaps in the literature have not been properly addressed in previous narrative reviews. In this review, current evidence regarding BDNF function, genetics and epigenetics, expression, and results from clinical trials is summarized, putting the literature into a translational perspective on MDD. In general, blood BDNF cannot be recommended for use as a biomarker in clinical practice. Moreover, future studies should expand the evidence with larger samples, use the serum or serum: whole blood concentration of BDNF as a more accurate measure of peripheral BDNF, and compare its change upon different treatment modalities of MDD.
... Recently the theory of neural-immune network has been proposed [25,26]. There were several reports on serum BDNF level in NPSLE patients, suggesting that BDNF was associated with the disease activity and brain parenchymal injury of NPSLE [27]. ...
Circulating brain-derived neurotrophic factor(BDNF) is mainly derived from lymphocytes. The serum BDNF level in SLE is decreased, and BDNF may be involved in the pathogenesis of systemic lupus erythematosus(SLE). Our aim is to determine whether BDNF affects the differentiation of CD4+T cells into regulatory T(Treg) or T helper 17(Th17). 30 patients were selected. TGF-β and IL-6 were added to induce differentiation of Treg and Th17. After co-cultured with BDNF, the percentages of CD4+CD25+CD127 low and CD4+IL-17A+ were detected by Flow cytometry, and the expression of Foxp3mRNA and RORγtmRNA were detected by Rt-PCR. Under the condition of Th17 and Treg polarization, after co-cultured with BDNF and TrkB IgG, the phosphorylation of Akt, mTORC1 and ERK1/2 were detected by western-blot, the percentages of CD4+CD25+CD127 low and CD4+IL-17A+ were detected by Flow cytometry. Under the condition of Th17 polarization, with the increase of BDNF concentration(60ng/ml, 120ng/ml, 350ng/ml), the percentages of CD4+IL-17A+ and the expression of RORγtmRNA were decreased(p<0.01; p<0.001). Under the condition of Treg polarization, the percentages of CD4+CD25+CD127 low and the expression of Foxp3mRNA were increased(p<0.001). Regardless of Th17 or Treg polarization, the phosphorylation of Akt, mTORC1 and ERK1/2 in the BDNF group were reduced(p<0.001), and the phosphorylation of Akt, mTORC1 in the TrkBIgG group were enhanced(p<0.001). BDNF down-regulates the differentiation of Th17 and promotes the differentiation of Treg in SLE through inhibiting the activation of PI3K-Akt-mTORC1 axis and ERK1/2 pathway. BDNF could play a certain role in maintaining the balance of Treg/Th17 ratio in SLE.
... NTS and its receptors are expressed by macrophages, T lymphocytes and dendritic cells. Besides, NTS also regulates neutrophil chemotaxis, cytokine synthesis, mast cell activation and nitric oxide (NO) generation (Otten et al. 1994;Vega et al. 2003). Apart from the well-studied role of ghrelin in energy balance and metabolic functions, studies investigated and reported the functional association of ghrelin on multiple organ systems such as central nervous, cardiovascular and immune systems (Dixit and Taub 2005). ...
Severe acute respiratory syndrome, coronavirus 2 (SARS-CoV-2), remains to be a threat across the globe. SARS-CoV-2 entry to the host-mediated by binding of viral spike protein to the Human angiotensin-converting enzyme 2 (ACE2) receptor. ACE2 is an essential member of the Renin-Angiotensin system (RAS) involved in maintaining blood pressure and vascular remodelling. Although ACE2 receptor is the entry point to the host, recent studies show activation of ACE2 to modulate the host to develop a suitable environment for its replication. However, the ACE2 activating the immune signals on SARS-CoV-2 attachment is still under investigation. We have used a systems biological approach to construct the host regulatory network upon SARS-CoV-2 attachment to the ACE2 receptor. Since lungs are the primary infection site, we integrate human lung gene expression profile along with the host regulatory network to demonstrate the altered host signalling mechanism on viral infection. Further, the network was functionally enriched to determine immune modulation in the network. We also used the proteomic database to assess the occurrence of similar signalling events in other human tissue that exhibits lineage of infection across different organs. The constructed network contains 133 host proteins with 298 interactions that directly or indirectly connect to the ACE2 receptor. Among 133 proteins, 29 found to be differentially regulated in the host lungs on SARS-CoV-2 infection. Altered proteins connect multiple proteins in a network that modulates kinase, carboxypeptidase and cytokine activity, leading to change in the host immune system, cell cycle, and signal transduction mechanism. Further investigation showed the presence of similar signalling events in the kidney, placenta, pancreas, testis, stomach, small intestine and adrenal gland suggesting the possible the mechanistic lineage of viral infection in other tissue. Overall, our results will help advance our understanding of the immune molecular regulatory network influenced by the ACE2 mediated interaction in other body tissues, which could help in finding the secondary health complications associated with SARS-CoV-2 infection.
... To the negative ones there pertain as follows: i) a low permeability of the blood-brain barrier being created by tight contacts of micro vessel intracerebral network, which became completed with a set of proteins (Claudine 1,5, Occludin and others), which are impermeable to hydrophilic low soluble compounds exceeding a diameter of 18 Å and a molecular weight of 180 Da. The vast majority of cytotoxic drugs pertain to them (Erdlenbruch et al., 2000;Kemper et al., 2004;Xie et al., 2005); ii) a weak selectivity of the concentration of cytostatic in the place of neoplasm (Cragnolini & Friedman, 2008); iii) an insufficiently studied mechanism of the action of traditional and new pharmacological agents, as well as their clearance, which hinders a reasonable estimation of the amount of molecules that come in direct contact with tumor cells (Gerstner & Fine, 2007;Ta et al., 2009); iv) a lack of unified schemes of medical product application, taking into account the morphological structure of complex heterogeneous neoplasias, stages of their malignancy, and individual sensitivity of the tumor cells to them and patient age (Alomar, 2010;Myung, et al., 2010); v) a symptomatic toxic side effect, reduced to a violation of general tissue metabolism and endocrine function, to immunity suppression, involvement in a destructive reaction of abnormal elements along with intact (healthy) cell ones, as well as the development of complications (acute arachnoiditis, meningo encephalopathy, renal failure, passing deviation from the motor areas, speech, vision, hearing, stop of growth, and cognitive deficits with reduced intelligence), what in totality leads to disability (Kemper et al., 2004;Vega et al., 2003); vi) a limited range of available medications. The postulates set forward underline the actuality of further improving of existing strategies and creating new ones for earlier diagnosis, prognosis and a more successful fight against cancer. ...
The problem of cancer embraces a lot of unresolved issues, among which there dominates
the problem of ascertainment of the mechanisms of uncontrolled growth and cellular spill of
tumor neoplasm, composed of dividing cancer cells and cancer stem cells (Schatton & Frank
MH, 2009; Schatton et al., 2009; Frank NY et al., 2010). It is impossible to answer the
question about a complete removal of the tumor tissue and simultaneous minimizing
the adverse effects of surgical and other manipulations while removing the tumor without
solving this problem. This is a particularly relevant goal for physicians who are engaged in
treatment of brain tumors. The destruction of nerve tissue nonaffected by tumor growth has
a negative impact on the integrative brain activity and at least on the central control of all
bodily functions and homeostasis maintenance. How is it possible to reduce by-effects of
major therapeutic technologies in neurooncology (surgical, radiological, chemotherapeutic),
having preserved or enhanced their selective tumor damaging action?
Since you choose chemotherapy as one of the ways to impact on tumor tissue, it is
impossible not to mention the commonly known toxic effect of chemotherapeutic agents on
all body tissues. Destroying the tumor cells, cytotoxic agents kill healthy cells and tissues.
Thus, local or systemic applying the chemotherapy leads inevitably to the destruction
of healthy brain cells in case of the tumor localization within the cranial cavity and the
spinal canal. Thus, one of the objectives of this work was to develop methodic of leveling
the general toxic effects of chemotherapy while strengthening their local destructive
effect on tumor tissue. What ways have been chosen to solve this problem?
... Dimerik polipeptid yapıdaki bu büyüme faktörleri, aksonlardaki ve dendritlerdeki dallanmaları düzenlerken sinapsların da stabilitesini sağlamaktadır (2). Nörotrofin ailesi başta merkezi sinir sistemi (MSS)'nden sentezlenmek üzere periferal sinir sistemi (PSS) nöronları ile nöronal olmayan periferal dokular gibi birçok hücre tipinde de sentezlendiği görülmektedir (3). ...
... The binding of NGF to TrkA can increase the effective concentration of NGF on the cell surface in the presence of p75 and increase its affinity by 25-fold [24]. In the absence of TrkA, the binding of NGF to p75 could induce apoptosis [25]. In addition, the number of primary and secondary follicles increased in p75 knockout mice [26]. ...
This study aimed to investigate whether chronic unpredictable mild stress (CUMS) affects follicular development in ovaries through the nerve growth factor (NGF)/high affinity nerve growth factor receptor, the Tropomyosin-related kinase A (TrkA) receptor, mediated signaling pathway and to reveal the relationship between chronic stress and premature ovarian insufficiency (POI) development. In this experiment, a CUMS rat model was constructed. It was found that serum estradiol (E2), anti-Mullerian hormone (AMH), and gonadotropin-releasing hormone (GnRH) levels decreased, while follicle-stimulating hormone (FSH) levels increased. The expression of NGF, TrkA, p75, and FSHR in ovarian tissue decreased significantly. The expression levels of TrkA and p75 protein in ovarian stroma and small follicles were observed by an immunofluorescence assay. In addition, the numbers of small follicles were significantly reduced. The expression of TrkA, p75, and FSHR in CUMS ovarian tissue was upregulated by exogenous NGF in vitro. Furthermore, after treatment with NGF combined with FSH, E2 secretion in ovarian tissue culture supernatant of CUMS rats also increased significantly. Therefore, CUMS downregulates NGF and TrkA and promotes the occurrence of POI in rats. Exogenous NGF and FSH can upregulate the NGF receptor, E2, and AMH in vitro, and improve the rat ovarian function. Future studies may associate these results with female population.
... 46 The functions of NGF and NT-3 are to mediate synaptic and morphological plasticity, as well as neuronal growth, survival, and differentiation. 47 The reduced serum levels of NGF and NT-3 in schizophrenia indicated that dysfunction of the developmental process involved in neurotrophic factors may contribute to the pathophysiology of schizophrenia. ...
Aims
The clinical features of schizophrenia can be mainly divided into two symptom domains: positive and negative. Patients in each symptom domain respond differently to treatments, and their prognoses vary accordingly. Serum protein factors, such as nerve growth factor (NGF), neurotrophin‐3 (NT‐3), interleukin‐6 (IL‐6), interleukin‐1beta (IL‐1β), and the calcium‐binding protein S100β, have been reported to be involved in the pathogenesis of schizophrenia. However, their roles in the positive and negative symptom domains have not been determined. In this study, we investigated whether the serum levels of these five protein factors differed among first‐episode drug‐naïve schizophrenia patients in each symptom domain and healthy controls.
Methods
Double‐antibody sandwich enzyme‐linked immunosorbent assays (ELISAs) were used to quantify the amounts of the five protein factors in serum.
Results
Compared with the levels in the controls (n = 60), increased serum levels of IL‐6, IL‐1β and S100β and decreased serum levels of NGF and NT‐3 were observed in first‐episode drug‐naïve schizophrenia patients. Additionally, the serum levels of IL‐6 and IL‐1β were significantly higher in schizophrenia patients characterized by negative symptoms (negative group, n = 37) than in those characterized by positive symptoms (positive group, n = 46). Based on multivariate regression analyses, serum levels of IL‐1β were positively associated with the negative symptom subscore of the Positive and Negative Syndrome Scale (PANSS) in the negative group and in all patients with schizophrenia.
Conclusions
The two subtypes of schizophrenia may have different pathological mechanisms. Patients characterized by negative symptoms probably have more serious disturbances in neuroimmunology.
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... CGRP receptor antagonists and anti-NGF antibody were reported to peripherally attenuate inflammatory pain and tolerance to the analgesic effect of morphine [16][17][18] . The role of the immune system in modulating pain pathways is not understood and under-researched with studies reporting sometimes conflicting data of its influence in neuropathic pain development [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] . ...
Background
Over 70% to 85% of men with advanced prostate cancer (PCa) develop bone metastases characterized by severe bone pain and increased likelihood of bone fracture. These clinical features result in decreased quality of life and act as a predictor of higher mortality. Mechanistically, the skeletal pathologies such as osteolytic lesions and abnormal osteoblastic activity drive these symptoms. The role of immune cells in bone cancer pain remains understudied, here we sought to recapitulate this symptomology in a murine model.
Methods
The prostate cancer bone metastasis‐induced pain model (CIBP) was established by transplanting a mouse prostate cancer cell line into the femur of immunocompetent mice. Pain development, gait dynamics, and the changes in emotional activities like depression and anxiety were evaluated. Animal tissues including femurs, dorsal root ganglion (DRG), and spinal cord were collected at killing and microcomputed tomography (μCT), histology/immunohistochemistry, and quantitative immunofluorescent analysis were performed.
Results
Mice receiving prostate cancer cells showed a significantly lower threshold for paw withdrawal responses induced by mechanical stimulation compared with their control counterparts. Zero maze and DigiGait analyses indicated reduced and aberrant movement associated emotional activity compared with sham control at 8‐weeks postinjection. The μCT analysis showed osteolytic and osteoblastic changes and a 50% reduction of the trabecular volumes within the prostate cancer group. Neurologically we demonstrated, increased calcitonin gene‐related peptide (CGRP) and neuronal p75NTR immune‐reactivities in both the projected terminals of the superficial dorsal horn and partial afferent neurons in DRG at L2 to L4 level in tumor‐bearing mice. Furthermore, our data show elevated nerve growth factor (NGF) and TrkA immunoreactivities in the same segment of the superficial dorsal horn that were, however, not colocalized with CGRP and p75NTR.
Conclusions
This study describes a novel immunocompetent model of CIBP and demonstrates the contribution of NGF and p75NTR to chronic pain in bone metastasis.
... These trophic/survival and proapoptotic actions of NTs are mediated by Trks and p75NTR respectively, but also depend on the ligands and the relative expression rate of the two receptors in target cells (Davies, 1997). NTs are synthesized and used in autocrine and paracrine manner by different cell types in the nervous, immune, and endocrine systems (Vega et al., 2003). NGF and BDNF are present in measurable quantity in blood and saliva (Lipps, 2000;Mandel et al., 2009;Tirassa et al., 2012). ...
Since 2004, vagus nerve stimulation (VNS) has been used in treatment-resistant or treatment-intolerant depressive episodes. Today, VNS is suggested as possible therapy for a larger spectrum of psychiatric disorders, including schizophrenia, obsessive compulsive disorders, and panic disorders. Despite a large body of literature supports the application of VNS in patients’ treatment, the exact mechanism of action of VNS remains not fully understood. In the present study, the major knowledges on the brain areas and neuronal pathways regulating neuroimmune and autonomic response subserving VNS effects are reviewed. Furthermore, the involvement of the neurotrophins (NTs) Nerve Growth Factor (NGF) and Brain Derived Neurotrophic Factor (BDNF) in vagus nerve (VN) physiology and stimulation is revised. The data on brain NGF/BDNF synthesis and in turn on the activity-dependent plasticity, connectivity rearrangement and neurogenesis, are presented and discussed as potential biomarkers for optimizing stimulatory parameters for VNS. A vagus nerve-neurotrophin interaction model in the brain is finally proposed as a working hypothesis for future studies addressed to understand pathophysiology of psychiatric disturbance.
Pancreatic ductal adenocarcinoma (PDAC) remains a formidable challenge in oncology, characterized by its immunosuppressive tumor microenvironment (TME) and resistance to immune checkpoint inhibitors (ICIs). This study leverages Mendelian randomization (MR) to elucidate the causal relationships between PDAC and a comprehensive array of immune cell traits, bacterial traits, inflammatory factors, and blood metabolites, aiming to uncover novel therapeutic targets and predictive biomarkers for PDAC. Utilizing datasets from large genome-wide association studies and employing the two-sample MR approach, we investigated the associations of 412 bacterial traits, 91 inflammatory factors, and 1400 blood metabolites with the risk of PDAC-related immune cell traits.
Our results highlight suggestive evidence of associations between PDAC and distinct immune cell phenotypes, revealing nuanced alterations across monocytes, T-cells, B-cells, dendritic cells, and myeloid-derived suppressor cells. These findings illustrate the paradoxical nature of immune activation and suppression within the PDAC TME, underscoring the critical balance between immune surveillance and evasion mechanisms. Additionally, we unearthed significant associations between PDAC risk and specific bacterial traits, shedding light on the microbiome's potential role in shaping the immunological landscape of PDAC. Inflammatory factors and blood metabolites also emerged as crucial players, with our analysis revealing their complex interplay in influencing PDAC risk, reflecting the dual role of inflammation in tumorigenesis and the profound impact of metabolic reprogramming on immune competency. And our study provides a granular view of the PDAC-immune interface, identifying key immune cell traits and their associations with PDAC. For instance, our findings suggest a detrimental reduction in various monocyte traits, alongside a decrease in B-cell populations, pointing to a systemic reshaping of the immune landscape in PDAC. Conversely, certain T-cell subsets showed increased associations, indicating potential targets for immunotherapeutic strategies. The bacterial trait associations, particularly with Collinsella and metabolic pathways like LACTOSECAT.PWY, highlight the gut microbiome's influence on immune modulation and PDAC pathogenesis.
This study advances our understanding of PDAC's resistance to immunotherapies by delineating the genetic and immunological underpinnings of its complex TME. The integration of genetic profiling with advances in immunotherapy holds promise for tailoring treatments to individual tumor characteristics and overcoming PDAC's immunosuppressive barriers. Our findings underscore the potential of personalized immunotherapy and the modulation of metabolic pathways as promising strategies for PDAC treatment, opening new avenues for research and clinical translation in the era of precision oncology.
B lymphocytes are immune cells studied predominantly in the context of peripheral humoral immune responses against pathogens. Evidence has been accumulating in recent years on the diversity of immunomodulatory functions that B cells undertake, with particular relevance for pathologies of the central nervous system (CNS). This review summarizes current knowledge on B cell populations, localization, infiltration mechanisms, and function in the CNS and associated tissues. Acute and chronic neurodegenerative pathologies are examined in order to explore the complex, and sometimes conflicting, effects that B cells can have in each context, with implications for disease progression and treatment outcomes. Additional factors such as aging modulate the proportions and function of B cell subpopulations over time and are also discussed in the context of neuroinflammatory response and disease susceptibility. A better understanding of the multifactorial role of B cell populations in the CNS may ultimately lead to innovative therapeutic strategies for a variety of neurological conditions.
Nerve growth factor (NGF) plays a dual role both in inflammatory states and cancer, acting both as a pro-inflammatory and oncogenic factor and as an anti-inflammatory and pro-apoptotic mediator in a context-dependent way based on the signaling networks and its interaction with diverse cellular components within the microenvironment. This report aims to provide a summary and subsequent review of the literature on the role of NGF in regulating the inflammatory microenvironment and tumor cell growth, survival, and death. The role of NGF in inflammation and tumorigenesis as a component of the inflammatory system, its interaction with the various components of the respective microenvironments, its ability to cause epigenetic changes, and its role in the treatment of cancer have been highlighted in this paper.
Citation: Terracina, S.; Ferraguti, G.; Tarani, L.; Fanfarillo, F.; Tirassa, P.; Ralli, M.; Iannella, G.; Polimeni, A.; Lucarelli, M.; Greco, A.; et al. Nerve Growth Factor and Autoimmune Diseases. Curr. Issues Mol. Biol. 2023, 45, 8950-8973. https://doi. Abstract: NGF plays a crucial immunomodulatory role and increased levels are found in numerous tissues during autoimmune states. NGF directly modulates innate and adaptive immune responses of B and T cells and causes the release of neuropeptides and neurotransmitters controlling the immune system activation in inflamed tissues. Evidence suggests that NGF is involved in the pathogenesis of numerous immune diseases including autoimmune thyroiditis, chronic arthritis, multiple sclerosis, systemic lupus erythematosus, mastocytosis, and chronic granulomatous disease. Furthermore, as NGF levels have been linked to disease severity, it could be considered an optimal early biomarker to identify therapeutic approach efficacy. In conclusion, by gaining insights into how these molecules function and which cells they interact with, future studies can devise targeted therapies to address various neurological, immunological, and other disorders more effectively. This knowledge may pave the way for innovative treatments based on NGF manipulation aimed at improving the quality of life for individuals affected by diseases involving neurotrophins.
Discogenic back pain, a subset of chronic back pain, is caused by intervertebral disc (IVD) degeneration, and imparts a notable socioeconomic health burden on the population. However, degeneration by itself does not necessarily imply discogenic pain. In this review, we highlight the existing literature on the pathophysiology of discogenic back pain, focusing on the biomechanical and biochemical steps that lead to pain in the setting of IVD degeneration. Though the pathophysiology is incompletely characterized, the current evidence favors a framework where degeneration leads to IVD inflammation, and subsequent immune milieu recruitment. Chronic inflammation serves as a basis of penetrating neovascularization and neoinnervation into the IVD. Hence, nociceptive sensitization emerges, which manifests as discogenic back pain. Recent studies also highlight the complimentary roles of low virulence infections and central nervous system (CNS) metabolic state alteration. Targeted therapies that seek to disrupt inflammation, angiogenesis, and neurogenic pathways are being investigated. Regenerative therapy in the form of gene therapy and cell-based therapy are also being explored.
Background:
Depression is a common psychiatric comorbidity among chronic dermatology patients. There is extreme lacking in the research studying biomarkers responsible for it. Both brain-derived neurotrophic factor (BDNF) and vitamin D have a significant role in the development of depression.
Aim:
To assess BDNF and vitamin D serum levels in different clinical verities of alopecia areata (AA) and vitiligo patients, correlating them with depression prevalence and quality of life.
Methods:
In all, 30 AA patients, 30 vitiligo patients, and 30 healthy volunteers were included. Both alopecia and vitiligo severity and activity were evaluated using the suitable clinical scores. Depression was assessed using Beck depression inventory (BDI) scale and quality of life was recorded using Dermatology Life Quality Index (DLQI). Both serum BDNF and vitamin D levels were investigated using ELISA.
Results:
In both alopecia and vitiligo patients, serum BDNF and serum vitamin D were significantly lower compared to controls (p = 0.001 for both). Both were associated and negatively correlated with BDI and DLQI. Regarding alopecia, they showed a significant decline in more sever disease and with longer disease duration. However, in vitiligo, BDNF (p = 0.001) and vitamin D (p = 0.03) correlated negatively with disease activity, but not with disease severity. Serum BDNF and vitamin D correlated positively with each other (p = 0.001) in both AA and vitiligo cases.
Conclusion:
The inverse association of both serum BDNF and vitamin D with depression, and the positive correlation noted between their serum levels, may indicate a potential combined effect of these two players on development of depression and its negative health-related outcomes.
In this review, an attempt was made to substantiate the possibility for neurotrophins to be involved in the development of immune tolerance based on data accumulated on neurotrophin content and receptor expression in the trophoblast and immune cells, in particular, in natural killer cells. Numerous research results are reviewed to show that the expression and localization of neurotrophins along with their high‐affinity tyrosine kinase receptors and low‐affinity p75NTR receptor in the mother‐placenta‐fetus system indicate the important role of neurotrophins as binding molecules in regulating the crosstalk between the nervous, endocrine and immune systems in pregnancy. An imbalance between these systems can occur with tumor growth and pathological processes observed in pregnancy complications and fetal development anomalies. This article is protected by copyright. All rights reserved
Degenerative disc disease of the lumbosacral spine is a very common medical problem. An episode of sciatica occurs at least once in the life of 60-90% of the human population.
A phenomenon that is closely related to the process of lowering the pH of the extracellular matrix degenerating the intervertebral disc (IVD) is the precipitation of calcium salts, especially pyrophosphate dehydrate and hydroxyapatite.
In such an altered environment of the IVD, we can observe an increased influx of monocytes, macrophages, T-lymphocytes, as well as non-immunocompetent cells, which are a source of cytokines, e.g., tumor necrosis alpha (TNF-α), interleukin- (IL-1β, IL-8). The above-mentioned mediators of an inflammatory condition contribute to an increase in the expression of Brain-Derived Neurotrophic Factor (BDNF) and Glial cell Derived Neurotrophic Factor (GDNF) in mast cells and chondrocytes, as well as to the descending transport of these mediators along the nerve endings.
In the process of degeneration of the IVD as a result of repeated and even slight injuries, there is damage to the connections of the endplate of the vertebral bodies with the IVD, which results in an impairment of the penetration of nutritional substances and water into the disc. As a consequence, there is an overexpression of the brain-derived neurotrophic factor GDNF, as well as neuromodulin (GAP-43) in the mast cells and chondrocytes of the IVDs, while descending transport of these mediators along the nerve fibers is also observed.
Our primary goal was to determine if leukocytes are a source of nerve growth factor (NGF) in mouse spleen. Noradrenergic nerves were localized to arteries and white pulp in normal spleens but only to arteries in ultra-immunodeficient R2G2 mice that lack leukocytes. NGF mRNA was detected in vascular cells and leukocytes of normal spleen, and several of the latter were T cells based on double labeling for NGF mRNA and CD3. Our findings indicate NGF is produced by vascular cells and to a lesser extent by leukocytes in spleen and provide support for pleiotropic actions in spleen and salivary glands.
Small extracellular vesicles (sEVs) including exosomes, carrying the CD20, could be involved in immunotherapy resistance in diffuse large B cell lymphoma (DLBCL). We have reported endogenous brain-derived neurotrophic factor/TrkB (tropomyosin-related kinase B) survival axis in DLBCL. Here, we performed a comparative study of sEV production by germinal centre B cell (GCB) and activated B cell (ABC)-DLBCL cell lines, and analysed TrkB activation on this process.
GCB (SUDHL4 and SUDHL6) and ABC (OCI-LY3, OCI-LY10 and U2932) cell lines were used. sEVs were characterised using nanoparticle tracking analysis technology and western blot. CD20 content was also analysed by enzyme-linked immunoassay, and complement-dependent cytotoxicity of rituximab was investigated. 7,8-Dihydroxyflavone (7,8-DHF) was used as a TrkB agonist. In vivo role of sEVs was evaluated in a xenograft model.
sEVs production varied significantly between DLBCL cells, independently of subtype. CD20 level was consistent with that of parental cells. Higher CD20 expression was found in sEVs after TrkB activation, with a trend in increasing their concentration. sEVs determined in vitro and in vivo protection from rituximab, which seemed CD20 level-dependent; the protection was enhanced when sEVs were produced by 7,8-DHF-treated cells.
DLBCL-derived sEVs have the differential capacity to interfere with immunotherapy, which could be enhanced by growth factors like neurotrophins. Evaluating the sEV CD20 level could be useful for disease monitoring.
Disease outbreak has continued to be a major challenge for shrimp aquaculture industry. In recent years, manipulation of gut microbiota has been shown to improve the health of host shrimp and disease resistance. Therefore, understanding how various factors can shape the gut microbiota of shrimp is crucial for future utilization of gut microbiota as tools for disease controls. The salinity of the rearing environment can potentially affect shrimp gut microbiota as well as the host-microbe interactions. The effects of salinity adaptation on intestinal microbiota and transcriptomes of juvenile black tiger shrimp Penaeus monodon were examined in this experiment.
Intestinal microbiota and transcriptomic profiles from juvenile black tiger shrimp of the same cohort adapted to three different salinity levels were examined using 16S rDNA amplicon sequencing and RNA sequencing, respectively. Shrimp were acclimatized from the original 20 ppt salinity to either 10 ppt or 30 ppt over a period of 10 days, and intestinal samples were collected on Day 0, Day 10, and Day 20 after reaching the target salinity. Across all salinity levels, the dominant phyla composition in the intestine of shrimp was relatively similar with Proteobacteria (83.4%), Bacteroidetes (8.1%), Planctomycetes (3.2%), Verrucomicrobia (2.5%), and Firmicutes (1.5%). The most abundant genus was Vibrio. While it can be found at all salinity levels, a relative abundance of Vibrio was lower at 10 ppt than at higher salinity. A shift toward the higher relative abundance of Vibrio ASVs belonging to the Harveyi clade was observed at higher salinity. On the other hand, the relative abundance of Shewanella was higher at 10 ppt than at higher salinity. Other dominant genera in the intestines not affected by the change in salinity were Pseudoaltermonas and Tenacibaculum. The shift in the rearing water microbiota with different salinity levels was also observed. The most abundant intestinal transcripts responding to different salinity levels based on GO classification were intracellular anatomical structure (cellular component), protein binding (molecular function), and organic substance metabolic process (biological function). Genes involved with stress and immune responses were differentially expressed, and correlations between potentially pathogenic Vibrio and genes relating to innate immunity and peritrophic matrix were observed.
The results confirmed the influence of rearing water salinity on both the intestinal microbiota and transcriptomes of shrimp. Efforts to shape the microbiota of aquatic animals should take into consideration the rearing salinity to ensure its efficacy. Using multi-omic platform allowed for better understanding of the microbiota and the host-microbe interaction, which will help support the sustainability of aquaculture production.
Cancer-induced bone pain (CIBP) is a refractory form of pain that has a high incidence in advanced tumors. Src protein tyrosine kinase is mainly composed of six domains, with two states of automatic inhibition and activation. The modular domain allows Src to conveniently regulate by and communicate with a variety of proteins, directly or indirectly participate in each step of the CIBP process. Src is beneficial to the growth and proliferation of tumor cells, and it can promote the metastases of primary tumors to bone. In the microenvironment of bone metastasis, it mainly mediates bone resorption, activates related peripheral receptors to participate in the formation of pain signals, and may promote the generation of pathological sensory nerve fibers. In the process of pain signal transmission, it mainly mediates NMDAR and central glial cells to regulate pain signal intensity and central sensitization, but it is not limited to these two aspects. Both basic experimentation and clinical research have shown encouraging potential, providing new ideas and inspiration for the prevention and treatment of CIBP.
In addition to the psychological depressive phenotype, major depressive disorder (MDD) patients are also associated with underlying immune dysregulation that correlates with metabolic syndrome prevalent in depressive patients. A robust integrative analysis of biological pathways underlying the dysregulated neural connectivity and systemic inflammatory response will provide implications in the development of effective strategies for the diagnosis, management and the alleviation of associated comorbidities. In the current study, focusing on MDD, we explored an integrative network analysis methodology to analyze transcriptomic data combined with the meta-analysis of biomarker data available throughout public databases and published scientific peer-reviewed articles. Detailed gene set enrichment analysis and complex protein–protein, gene regulatory and biochemical pathway analysis has been undertaken to identify the functional significance and potential biomarker utility of differentially regulated genes, proteins and metabolite markers. This integrative analysis method provides insights into the molecular mechanisms along with key glycosylation dysregulation underlying altered neutrophil-platelet activation and dysregulated neuronal survival maintenance and synaptic functioning. Highlighting the significant gap that exists in the current literature, the network analysis framework proposed reduces the impact of data gaps and permits the identification of key molecular signatures underlying complex disorders with multiple etiologies such as within MDD and presents multiple treatment options to address their molecular dysfunction.
Fibronectin type III domain-containing-5 (Fndc5) is a trans-membrane protein which is involved in a variety of cellular events including neural differentiation of mouse embryonic stem cells (mESCs) as its knockdown and overexpression diminishes and facilitates this process, respectively. However, downstream targets of Fndc5 in neurogenesis are still unclear. Neurotrophins including NGF, BDNF, NT-3, and NT-4 are the primary regulators of neuronal survival, growth, differentiation, and repair. These biomolecules exert their actions through binding to two different receptor families, Trk and p75NTR. In this study, considering the fact that neurotrophins and their receptors play crucial roles in neural differentiation of ESCs, we sought to evaluate whether knockdown of Fndc5 decreased neural differentiation of mESCs by affecting the neurotrophins and their receptors expression. Results showed that at neural progenitor stage, the mRNA and protein levels of BDNF, Trk, and p75NTR receptors decreased following the Fndc5 knockdown. In mature neural cells, still, the expression of Trk and p75NTR receptors at mRNA and protein levels and BDNF and NGF expression only at protein levels showed a significant decrease in Fndc5 knockdown cells compared to control groups. Taken together, our results suggest that decreased efficiency of neural differentiation following the reduction of Fndc5 expression could be attributed to decreased levels of NGF and BDNF proteins in addition to their cognate receptors.
As the population ages, obesity and metabolic complications as well as neurological disorders are becoming more prevalent, with huge economic burdens on both societies and families. New therapeutics are urgently needed. Nerve growth factor (NGF), first discovered in 1950s, is a neurotrophic factor involved in regulating cell proliferation, growth, survival, and apoptosis in both central and peripheral nervous systems. NGF and its precursor, proNGF, bind to TrkA and p75 receptors and initiate protein phosphorylation cascades, resulting in changes of cellular functions, and are associated with obesity, diabetes and its complications, and Alzheimer's disease. In this article, we summarize changes in NGF levels in metabolic and neuronal disorders, the signal transduction initiated by NGF and proNGF, the physiological and pathophysiological relevance, and therapeutic potential in treating chronic metabolic diseases and cognitive decline.
The effect of 2.5S nerve growth factor (NGF) on survival, phagocytosis, and superoxide production of murine neutrophils was examined and compared with the effects of interleukin-3 (IL-3) and recombinant GM colony-stimulating factor (rGM-CSF). NGF enhanced the viability of neutrophils isolated from peripheral blood and peritoneal cavity in a dose-dependent way. IL-3 50 U/mL had no effect. rGM-CSF 50 U/mL had an effect similar to that of 50 ng/mL NGF. NGF also enhanced the phagocytosis of hydrophilic microspheres by peritoneal neutrophils, and the activity of NGF was greater than that of IL-3 or rGM-CSF. NGF enhanced the superoxide production induced by phorbol 12-myristate 13- acetate (PMA), which acts at postreceptor sites, and that induced by opsonized zymosan, a receptor-mediated ligand. The stimulating activity of NGF was largely comparable to that of rGM-CSF. The present data show that NGF bound to neutrophils enhances their survival, phagocytosis, and superoxide production. Thus, we postulate that NGF plays an important role in the inflammatory processes.
Nerve growth factor causes mediator release from rat peritoneal mast cells in the presence of lysophosphatidylserine. We have investigated the neurotrophin and receptor specificity involved in this response. Nerve growth factor produced a dose-dependent release of [C-14]serotonin in the presence of lysophosphatidylserine with an EC50 of approximately 1 nM. Incubation with brain-derived neurotrophic factor and neurotrophin-3 did not produce a response. Northern blot analysis with probes for low affinity nerve growth factor receptor (p75), trkA, trkB, and trkC demonstrated a detectable signal for trkA only. Western blots of trkA immunoprecipitates from mast cell culture lysates, probed with anti-phosphotyrosine antibodies, demonstrated expression of functional TrkA protein. To determine whether p75, trkB, or trkC mRNA was present in amounts below the limit of detection for Northern analysis, a sensitive reverse transcriptase polymerase chain reaction protocol was used; again rat peritoneal mast cells demonstrated only trkA. The predominant form of trkA message expressed in rat peritoneal mast cells was smaller than the neuronal form. An 18-nucleotide exon (coding for 6 amino acids in the extracellular domain) in the neuronal message was not found in the predominant mast cell trkA message. PC12 cells, a rat pheochromocytoma cell line, and dissociated rat sympathetic neurons showed both trkA and p75, but not trkB or trkC. Anterior pituitary expressed both trkB and trkC, but not trkA. To confirm the lack of expression of p75 on mast cells, I-125-nerve growth factor was chemically cross-linked to mast cells or PC12 cells and then immunoprecipitated with a monoclonal antibody specific for p75, 192-IgG; no p75 was detected. Thus, mediator release from rat peritoneal mast cells by nerve growth factor was specific and not a general property of neurotrophins, and the response was modulated through the trkA proto-oncogene. To our knowledge, this is the first description of a bone marrow-derived cell type that expresses trkA at both the mRNA and protein levels. These data provide further evidence that p75 is not necessary for nerve growth factor signal transduction.
The effect of nerve growth factor (NGF) on proliferation/differentiation of mast cells was investigated in vitro. Although NGF alone neither supported colony formation of bone marrow-derived cultured mast cells (BMCMC) nor induced development of mast cell colonies from nonadherent bone marrow cells (NBMC), addition of NGF to the suboptimal dose of interleukin 3 (IL3) significantly increased the numbers of mast cell colonies produced by BMCMC or NBMC in methylcellulose. When stimulated by IL3 alone, cells in mast cell colonies were not stained by berberine sulfate, a fluorescent dye. In contrast, mast cells developing in methylcellulose cultures obtaining both 11,3 and NGF were stained by berberine sulfate. The fluorescence was abolished by the treatment of heparinase but not of chondroitinase ABC, suggesting that mast cells stimulated by 11,,3 and NGF produced and stored heparin proteoglycan. The histamine content of BMCMC maintained by IL-3 was also increased by addition of NGF. Since BMCMC showed mucosal mast cell-like phenotype, NGF appeared to induce the phenotypic change to connective tissue-type mast cells (CTMC). In the culture containing BMCMC, 3T3 fibroblasts, and IL-3, the phenotypic change of BMCMC to CTMC was observed as well. Since NGF was detected in this coculture and since addition of anti-NGF monoclonal antibody suppressed the phenotypic change, NGF produced by fibroblasts appeared to induce the phenotypic change. Neither BMCMC alone nor IL3 alone increased the concentration of NGF. Therefore, there is a possibility that BMCMC stimulated by IL3 may induce the production and/or release of NGF by fibroblasts .
Nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3 (NT-3) are the three members of the neurotrophin family known to exist in mammals. Recently, a fourth neurotrophin (designated neurotrophin-4 or NT-4), which shares all of the features found in the mammalian neurotrophins, has been identified in Xenopus and viper. We used sequences specific to the Xenopus/viper NT-4 to isolate a neurotrophin from both human and rat genomic DNA that appears to represent the mammalian counterpart of Xenopus/viper NT-4. Human NT-4 as well as a human NT-4 pseudogene colocalize to chromosome 19 band q13.3. Mammalian NT-4 has many unusual features compared to the previously identified neurotrophins and is less conserved evolutionarily than the other neurotrophins. However, mammalian NT-4 displays bioactivity and trk receptor specificity similar to that of Xenopus NT-4.
Decapsulated cysts of Artemia subjected to different heat treatments (40, 60, 80 and 96 °C) were fed to African catfish Clarias gariepinus larvae. Heated cysts, untreated cysts and live Artemia nauplii as control constituted the experimental diets. Protein denaturation and solubility, total alkaline protease and specific trypsin activities in the cyst diets were evaluated. The growth of catfish larvae and the proteolytic activity of larval samples during development were also determined. Heat treatment of cysts increased protein denaturation and decreased protein solubility. The protease activity in the cyst diets decreased with higher heating temperatures. The growth of catfish larvae differed according to the diet; higher fish growth was achieved with nauplii and cysts heated at 40 °C. The digestive enzyme activity in larval samples remained similar in all dietary treatments during larval development. The quality of food protein and the way this protein is processed might be more important for successful larval growth than exogenous enzyme supply.
Nerve growth factor (NGF) was originally considered as a trophic factor for peripheral sympathetic and sensory neurones; however, recent reports indicate that NGF may induce proliferation of immune and haematopoietic cells. Histochemical studies conducted in human spleen and lymph nodes have suggested the presence of NGF receptor (NGF-R) immunoreactive elements in secondary follicles; however the nature of the cells bearing the NGF-R in lymphoid tissue has not been determined. In this paper we report the results of an immunohistochemical study conducted on mucosa associated lymphoid tissue. Using a specific monoclonal antibody to human NGF-R (mAb 20.4) we observed an NGF-R-immunoreactive population in all secondary lymphoid follicles examined. Double immunostaining revealed that this population was composed of follicular dendritic cells (FDC); lymphoid cells within the germinal centres did not appear to be 20.4 immunoreactive. Cell suspensions from tonsillar follicles also contained NGF-R immunopositive dendritic cells which were enriched by a 20.4 labelled magnetic bead procedure, revealing cells with the morphological characteristics of FDC. Mononuclear cells from human peripheral blood did not contain any NGF-R-immunoreactive elements using our techniques.
Neural crest cell derivatives have been suggested to be involved in thymus development. We established nonlymphoid thymic stromal cell cultures capable of supporting T-cell differentiation. In these nonlymphoid cell cultures, we identified cells with phenotypic and biochemical markers specific for neuronal cells. Neurofilament mRNA and 68- and 160-kDa neurofilament proteins, as well as 74-kDa synapsin I isoform, were expressed in many of the cultured cells. For example, neurofilament immunoreactivity was detected in 20-30% of the cells. To see whether thymic neuronal-like cells were involved in a neural differentiation pathway, we investigated the effect of nerve growth factor (NGF) and interleukin 6 (IL-6), two known neurotrophic factors. The expression of the above-described neural markers was enhanced by NGF and IL-6, which we report to be produced in an autocrine way by thymic stromal cell cultures. Finally, we found that IL-6 gene expression in these cell cultures was enhanced by NGF. Evidence is thus offered of a neuromodulatory loop within the thymic stromal cell population supported by local production of NGF and IL-6 and involving neural cell elements. Interestingly, IL-6, which is known to be implicated in thymocyte differentiation, also displays a neuromodulatory activity on thymic stromal cells, suggesting a multivalent role for this cytokine within the thymus.
The neurotrophins, of which nerve growth factor (NGF) is the best known example, support the survival and differentiation of chick embryo sensory neurons at extremely low concentrations, 10(-12) M or less. These same neurons display two different classes of neurotrophin receptors with dissociation constants of 10(-11) M and 10(-9) M, respectively, implying that only low occupancy of the higher affinity receptor is required to mediate the biological actions of the neurotrophins. Two structurally unrelated receptors have now been characterized for NGF, and one of them, p75NGFR, serves as a receptor for all the known neurotrophins. This is the receptor with a dissociation constant of 10(-9) M. The second NGF receptor is a member of the trk family of tyrosine kinase receptors, p140trkA. Other members, p145trkB and p145trkC, are receptors for brain-derived neurtrophic factor (BDNF) and neurotrophin-4 (NT-4) and neurotrophin-3 (NT-3), respectively, when assayed in fibroblasts. The specificity of neurotrophin binding to these receptors appears to be much higher in neurons than in the non-neuronal cells. The receptor p140trkA has many of the properties of the higher affinity class of NGF receptors, and is able to mediate survival and differentiation of the PC12 cell line, and cell growth and transformation in fibroblast cells. On the other hand, expression of p75NGFR in several types of cells displaying p140trkA induces a component of higher affinity NGF binding not seen in its absence. Since it is unlikely that p75NGFR and p140trkA interact at the level of the receptors, the crosstalk between receptors probably occurs through their signal transduction mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)
Neurotrophin-3 (NT-3) has low-affinity (Kd = 8 x 10(-10) M), as well as high-affinity receptors (Kd = 1.8 x 10(-11) M) on embryonic chick sensory neurons, the latter in surprisingly high numbers. Like the structurally related proteins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), NT-3 also binds to the low-affinity NGF receptor, a molecule that we suggest to designate low-affinity neurotrophin receptor (LANR). NT-3 dissociates from the LANR much more rapidly than BDNF, and more slowly than NGF. The binding of labelled NT-3 to the LANR can be reduced by half using a concentration of BDNF corresponding to the Kd of BDNF to the LANR. In contrast, the binding of NT-3 to its high-affinity neuronal receptors can only be prevented by BDNF or NGF when used at concentrations several thousand-fold higher than those corresponding to their Kd to their high-affinity neuronal receptors. Thus, specific high-affinity NT-3 receptors exist on sensory neurons that can readily discriminate between three structurally related ligands. These findings, including the remarkable property of the LANR to bind three related ligands with similar affinity, but different rate constants, are discussed.
The effect of nerve growth factor (NGF) on proliferation/differentiation of mast cells was investigated in vitro. Although NGF alone neither supported colony formation of bone marrow-derived cultured mast cells (BMCMC) nor induced development of mast cell colonies from nonadherent bone marrow cells (NBMC), addition of NGF to the suboptimal dose of interleukin 3 (IL-3) significantly increased the numbers of mast cell colonies produced by BMCMC or NBMC in methylcellulose. When stimulated by IL-3 alone, cells in mast cell colonies were not stained by berberine sulfate, a fluorescent dye. In contrast, mast cells developing in methylcellulose cultures obtaining both IL-3 and NGF were stained by berberine sulfate. The fluorescence was abolished by the treatment of heparinase but not of chondroitinase ABC, suggesting that mast cells stimulated by IL-3 and NGF produced and stored heparin proteoglycan. The histamine content of BMCMC maintained by IL-3 was also increased by addition of NGF. Since BMCMC showed mucosal mast cell-like phenotype, NGF appeared to induce the phenotypic change to connective tissue-type mast cells (CTMC). In the culture containing BMCMC, 3T3 fibroblasts, and IL-3, the phenotypic change of BMCMC to CTMC was observed as well. Since NGF was detected in this coculture and since addition of anti-NGF monoclonal antibody suppressed the phenotypic change, NGF produced by fibroblasts appeared to induce the phenotypic change. Neither BMCMC alone nor IL-3 alone increased the concentration of NGF. Therefore, there is a possibility that BMCMC stimulated by IL-3 may induce the production and/or release of NGF by fibroblasts.
The increasing knowledge of the pathogenic mechanisms involved in cancer cell growth has enabled the implementation of mechanism based drug design approaches rather than the more conventional nonspecific approaches. Drugs that interfere with cellular signal transduction pathways are currently a major focus in development of newer therapeutic technologies in oncology. The therapeutic utility of potent and selective tyrosine kinase inhibitors in oncologic applications has become widely recognized for several years, however targeting neurotrophin receptors as a molecular target driven approach has only recently been realized. This review presents the hypothesis of the neurotrophin-trk receptors as a viable molecular target for medicinal chemical intervention in tumor biology, followed by an overview of the pre-clinical studies which culminated in the advancement of the first potent trk tyrosine kinase inhibitor CEP-2563 (KT-8391), and the orally active K -252a analog, CEP-701 (KT-5555) into clinical evaluation.
It is now well established that neurotrophins play a crucial role in the development of the nervous system. However, there is increasing evidence that the function of neurotrophins persists throughout adulthood. The broad scope of neurotrophin action is well documented in the case of nerve growth factor (NGF) and its effect on nociceptors and nociception. Here, we review the evidence for these multiple roles for NGF. Two manipulations influencing NGF levels are discussed in detail. The first involves the use of transgenic mice that overexpress or underexpress neurotrophins. A second strategy involves administration of NGF or its antibody in vivo to increase or decrease its level. During prenatal development, NGF is required for survival of nociceptors. In the early postnatal period, NGF is required for expression of the appropriate nociceptor phenotype. In adults, NGF acts as an important intermediate in inflammatory pain, contributing to both peripheral and central sensitization. The sensitization of peripheral nociceptors can be very rapid and can involve non‐neural cells such as mast cells, neutrophils, fibroblasts, and macrophages. Recent evidence indicates that other neurotrophins also play key supporting roles in the development of nociceptors (e.g., NT‐3) and in inflammatory pain (e.g., BDNF, NT‐4/5). Furthermore, molecules from other superfamilies (e.g., GDNF) also are required to assure survival of certain classes of nociceptors. The diverse effects of neurotrophins on nociceptive processing emphasize their broad importance in the development and function of the nervous system. Microsc Res Tech 45:252–261, 1999. © 1999 Wiley‐Liss, Inc.
The aggressive and highly metastatic behavior observed in pancreatic ductal adenocarcinoma (PDAC) may be due to autocrine and/or paracrine interactions (tumor/stromal) involving altered expression of peptide growth factors and their corresponding receptors. The neurotrophin (NT) growth factor family and their cognate receptors have been demonstrated to play a role in the invasiveness, chemotactic behavior and tumor cell survival of both neuronal and non‐neuronal cancers. We hypothesized that aberrant expression of the NTs and/or the Trk receptors may contribute to the malignant phenotype of PDAC, specifically tumor cell invasiveness, through autocrine and/or paracrine interactions. In this study, we examined the expression of NTs, Trks and p75NGFR by immunohistochemical and in situ hybridization analyses in both normal (n = 14) and neoplastic pancreas (n = 47) and PDAC‐derived cell lines (n = 6). Further, we evaluated the effects of various NTs on the in vitro invasive and chemotactic behavior on 6 human PDAC‐derived cell lines in a modified Boyden chamber assay. Brain‐derived nerve growth factor (BDNF), NT‐3, NT‐4/5 and Trks A, B and C exhibited diffuse cytoplasmic and membranous immunostaining patterns in both the ducts and the acini of the exocrine pancreas and the islets of the endocrine pancreas of both normal and PDAC specimens. NT expression was primarily within the stromal compartment of the tumor, while Trk expression was weak or absent. We observed a 68%, 64% and 66% increase in the expression of Trks A, B and C, respectively, in the ductal elements of the PDAC samples examined compared with the normal adjacent tissue. Invasiveness of 4 of 6 PDAC cell lines was significantly inhibited (p < 0.05) when the cells were incubated with 100 ng/ml NT. However, when select cell lines were incubated with lower concentrations of NT‐3 and BDNF (0, 1, 5, 25 and 50 ng/ml), invasiveness was significantly stimulated (p < 0.05) through the Matrigel matrix. Collectively, our data suggest the possibility that paracrine and/or autocrine NT‐Trk interactions may influence the phenotype (possibly the invasive behavior) of PDAC. Int. J. Cancer 81:417–427, 1999. © 1999 Wiley‐Liss, Inc.
The expression of the low-affinity NGF receptor (p75) and the trkA proto-oncogene product was analyzed in a series of human hematopoietic cell lines at protein and RNA levels. We did not detect any form of NGF receptor in cell lines displaying a myelomonocytic phenotype (HL60 and U937). In contrast, cells displaying a more immature erythroleukemic phenotype (TF1 and K562) expressed TrkA in the absence of detectable p75. Scatchard analysis showed a single high-affinity site for NGF (kd = 10(-10) mol/L), with a copy number ranging from 300 to 3,000 sites per cell depending on the studied cell line. In addition, NGF induced autophosphorylation of TrkA and could substitute for granulocyte- monocyte colony-stimulating factor to trigger the proliferation of the TF1 cell line, with a half-maximal signal observed at 50 pmol/L, indicating that p75 is not required for DNA synthesis in this cell line. The physiologic relevance of NGF in early hematopoiesis was confirmed by showing that 12% to 15% of progenitor blood cells from mice treated with 5-fluorouracil expressed TrkA and that these cells could be induced to proliferate and differentiate in response to NGF in association with macrophage colony-stimulating factor. Our study demonstrates for the first time that trkA proto-oncogene expression and activation is not restricted to the nervous system, but is also an important element in early hematopoiesis.
Two anti-nerve growth factor receptor (LNGFR or p75NGFR) antibodies, Me20.4 and Me8211, label stromal cells with dendritic features in fresh smears and in formalin-fixed, paraffin-embedded human bone marrow (BM). The LNGFR+ cells have an oval nucleus, a scanty cytoplasm with long dendrites that intermingle with the hematopoietic cells, line the abluminal side of sinus endothelial cells, and provide the scaffold for the hematopoietic marrow. At the electron microscopy level, the immunogold tag labels the body and the long branching dendrites of fibroblast-like cells with scanty cytoplasm containing mitochondria, endoplasmic reticulum, and dense bodies. The LNGFR+ cells are positive for alkaline phosphatase, reticulin, collagen III, vimentin, TE-7, and CD13 but negative for endothelial (vWF, CD34, Pal-E), neural (CD56, neurofilament) and leukocyte markers (CD45, CD68). The LNGFR+ stromal cells appear in the fetal BM before the hematopoietic activity begins, originate from the vessel adventitia, and radiate in the Bm cavity. Long-term BM culture (LTBMC) in vitro contain LNGFR+ stromal cells. We document the presence of RNA message for the low- (LNGFR) and the high- affinity NGF receptor (NTRK1) by using RT-PCR on fresh BM aspirate and on LTBMC. BM biopsies from patients with hematologic fibrogenic diseases and in cytokine-treated cancer patients are evaluated for LNGFR+ cells: the amount of stained cells is correlated with the traditional reticulin stain in cases of myelofibrosis, therapy-related myelodysplasia, leukemia, and detected an increase of stromal cells in cytokine-treated patients. The anti-LNGFR antibodies represent a specific membrane marker for the adventitial reticular cells (ARC) of the human marrow and allow precise evaluation and quantitation of this important BM microenvironment component in vivo and in vitro.
We have recently shown that nerve growth factor (NGF) promotes human granulopoiesis, specifically augmenting basophilic cell differentiation observed in methylcellulose hematopoietic colony assays of human peripheral blood. Because the NGF effect was seen in the presence of conditioned medium derived from a human T-cell line (Mo-CM) containing granulocyte-macrophage colony-stimulating factor (GM-CSF), we examined interactions of purified NGF and recombinant human GM-CSF (rhGM-CSF) on granulocyte growth and differentiation. rhGM-CSF stimulated a dose- dependent increase in methylcellulose colony growth at concentrations between 0.1 U/mL and 10 U/mL, and in the presence of NGF at 500 ng/mL this effect was enhanced. The number of basophilic cell colony-forming units (CFU-Baso) and histamine-positive colonies increased synergistically when NGF was added to rhGM-CSF. Furthermore, because Mo- CM acts with sodium butyrate to promote basophilic differentiation of alkaline-passaged myeloid leukemia cells, HL-60, we also examined the interaction of NGF and Mo-CM or rhGM-CSF using this assay. In the presence of NGF, Mo-CM at concentrations of 0.5% to 20% vol/vol, and rhGM-CSF at concentrations of 0.1 U/mL to 100 U/mL synergistically increased histamine production by butyrate-induced, alkaline-passaged HL-60 cells; this was associated with the appearance of metachromatic, tryptase-negative, IgE receptor-positive cells. The effects of rhGM-CSF or Mo-CM were completely abrogated by a specific anti-rhGM-CSF neutralizing antibody in methylcellulose, with or without NGF; the NGF synergy with rhGM-CSF in the HL-60 assay was also inhibited by either anti-rhGM-CSF or anti-NGF antibody. These studies support the notion that differentiation in the basophilic lineage may be enhanced by NGF acting to increase the number of GM-CSF-responsive basophilic cell progenitors.
Congenital insensitivity to pain with anhidrosis (CIPA) is an autosomal-recessive disorder characterized by recurrent episodes of unexplained fever, anhidrosis (absence of sweating) and absence of reaction to noxious stimuli, self-mutilating behavior, and mental retardation. The genetic basis for CIPA is unknown. Nerve growth factor (NGF) induces neunte outgrowth and promotes survival of embryonic sensory and sympathetic neurons. Mice lacking the gene for TrkA, a receptor tyrosine kinase for NGF, share dramatic phenotypic features of CIPA, including loss of responses to painful stimuli, although anhidrosis is not apparent in these animals. We therefore consider the human TRKA homologue as a candidate for the CIPA gene. The mRNA and genomic DNA encoding for TRKA were analyzed in three unrelated CIPA patients who had consanguineous parents. We detected a deletion-, splice-, and a missense-mutation in the tyrosine kinase domain in these three patients. Our findings strongly suggest that defects in TRKA cause CIPA and that the NGF-TrkA system has a crucial role in the development and function of the nociceptive reception as well as establishment of thermorégulation via sweating in humans. These results also implicate genes encoding other TRK and neurotrophin family members as candidates for developmental defect(s) of nervous system.
The role of nerve growth factor (NGF), a potent mediator acting in the development and differentitation of both neuronal and immune cells, was examined in a mouse model of allergic asthma. NGF-positive cells were detected in the inflammatory infiltrate of the lung and enhanced levels of NGF were detected in serum and broncho-alveolar lavage fluids. Mononuclear cells in inflamed airway mucosa as well as broncho-alveolar macrophages were identified as one source of NGF production. Splenic mononuclear cells from allergen-sensitized mice produced NGF in response to allergen. They responded to exogenously added NGF with a dose-dependent increase in IL-4 and IL-5 production and augmented IgE and IgG1 synthesis. In contrast, IFN-γ and IgG2a levels remained unaffected. The effects were NGF specific, since they could be blocked by an anti-NGF-antibody. Nasal application of anti-NGF to allergen-sensitized mice significantly reduced IL-4 and prevented development of airway hyperreactivity. These results show that allergic airway inflammation is accompanied by enhanced local NGF production that acts as an amplifier for Th2 effector functions and plays an important role in the development of airway hyperreactivity. Therefore it is suggested that NGF may serve as a link between the immune and nerve system.
The aim of this study was to investigate production and cellular sources of brain-derived neurotrophic factor (BDNF) production in allergic asthma. For this purpose a mouse model of chronic and severe ovalbumin (OVA)-induced airway inflammation was developed. Allergen-exposed mice developed elevated immunoglobulin E titers; airway inflammation with influx of lymphocytes, monocytes, and eosinophils; and airway hyperresponsiveness. In addition to an influx of inflammatory cells, interleukin (IL)-4 and IL-5 production were enhanced, macrophages showed morphologic signs of activation, and airway epithelium was thickened and displayed a goblet-cell hyperplasia with a marked mucus production. BDNF was detected using in situ hybridization and enzyme-linked immunosorbent assay. Constitutive expression of BDNF messenger RNA (mRNA) was observed in the respiratory epithelium of sensitized and nonsensitized mouse lungs. In addition, BDNF mRNA was detected in airway inflammatory infiltrations and bronchoalveolar lavage fluid (BALF) cells of OVA-sensitized and aerosol-challenged mice. Highest BDNF protein levels were detected in BALF after long-term allergen aerosol exposure. Analysis of BDNF production by isolated lymphocyte subsets revealed T but not B cells as a cellular source of BDNF. In addition, activated alveolar macrophages were identified as BDNF-positive cells. These data indicate that in allergic airway inflammation BDNF production is upregulated and immune cells serve as a source of BDNF.
The aim of this study was to investigate production and cellular sources of brain-derived neurotrophic factor (BDNF) production in allergic asthma. For this purpose a mouse model of chronic and severe ovalbumin (OVA)-induced airway inflammation was developed. Allergen-exposed mice developed elevated immunoglobulin E titers; airway inflammation with influx of lymphocytes, monocytes, and eosinophils; and airway hyperresponsiveness. In addition to an influx of inflammatory cells, interleukin (IL)-4 and IL-5 production were enhanced, macrophages showed morphologic signs of activation, and airway epithelium was thickened and displayed a goblet-cell hyperplasia with a marked mucus production. BDNF was detected using in situ hybridization and enzyme-linked immunosorbent assay. Constitutive expression of BDNF messenger RNA (mRNA) was observed in the respiratory epithelium of sensitized and nonsensitized mouse lungs. In addition, BDNF mRNA was detected in airway inflammatory infiltrations and bronchoalveolar lavage fluid (BALF) cells of OVA-sensitized and aerosol-challenged mice. Highest BDNF protein levels were detected in BALF after long-term allergen aerosol exposure. Analysis of BDNF production by isolated lymphocyte subsets revealed T but not B cells as a cellular source of BDNF. In addition, activated alveolar macrophages were identified as BDNF-positive cells. These data indicate that in allergic airway inflammation BDNF production is upregulated and immune cells serve as a source of BDNF.
In this study we examined the expression of neurotrophins and their receptors in mouse macrophages and the effects of the neurotrophins on nitric oxide secretion. Macrophages expressed TrkB and TrkC but not BDNF, NT-3 or NT-4. LPS induced up-regulation of TrkB and TrkC and of BDNF and NT-3 expression. Treatment of macrophages with NT-3 increased the secretion of nitric oxide in LPS-treated macrophages and this increase was blocked by K252a, a Trk kinase inhibitor. In contrast, BDNF and NT-4 had no significant effects on the induction of nitric oxide. Our results suggest that NT-3 play important roles in the function of macrophages during inflammatory responses and in tissue repair.
Using neonatal rats we investigated the role of the thymus and thymosin-α1 (T-α1) in brain NGF levels, NGF receptor (p75NGFr) expression, as well as the activity of choline acetyl-transferase, a cholinergic enzyme regulated by NGF. It is shown that early postnatal thymectomy causes a decrease in NGF in the hippocampus and cortex and p75NGFr distribution in the basal forebrain cholinergic neurons (FBCN). Intracerebral T-α1 injection in thymectomized animals induces a recovery, albeit not complete, of both NGF and p75NGFr. These findings indicate that thymectomy affects both the brain NGF producing and responding cells and that T-α1 may be one of the thymic hormones involved in the regulation of cerebral NGF synthesis.
Nerve growth factor (NGF) is a neurotropic polypeptide which has broad biological activity other than support of growth and survival of sympathetic, sensory and central neurons. NGF promotes rat mast cell hyperplasia in vivo and human granulopoiesis in vitro, selectively augmenting basophil/mast cell differentiation in the presence of T cells or conditioned medium derived from a human T cell line (Mo-CM), a source of granulocyte-macrophage colony-stimulating factor (GM-CSF). NGF also synergizes with GM-CSF to promote human basophil/mast cell differentiation in both methylcellulose and suspension cultures of myeloid progenitors. In the current studies, we examined the interactions of NGF and several cytokines considered to be involved in human basophil/mast cell and eosinophil growth and differentiation, including interleukin (IL)-3, IL-4, IL-5, GM-CSF and granulocyte colony-stimulating factor (G-CSF). NGF synergistically enhanced IL-5 induced dose-dependent increases in histamine content and basophilic cell differentiation of myeloid leukemic HL-60 cells, but was only additive to similar effects of IL-3. In contrast, IL-4 and G-CSF did not promote basophilic differentiation of HL-60 cells in the presence or absence of NGF. Various combinations of GM-CSF, G-CSF, IL-3, IL-4 and IL-5 could not reproduce the synergy observed between NGF and either IL-5 or GM-CSF. NGF appears to represent a class of lineage-specific co-factors, in this case being involved in GM-CSF- or IL-5-induced basophilic lineage differentiation, thus contributing to tissue inflammation or repair.Copyright © 1990 S. Karger AG, Basel
The role of nerve growth factor (NGF), a potent mediator acting in the development and differentitation of both neuronal and immune cells, was examined in a mouse model of allergic asthma. NGF-positive cells were detected in the inflammatory infiltrate of the lung and enhanced levels of NGF were detected in serum and broncho-alveolar lavage fluids. Mononuclear cells in inflamed airway mucosa as well as broncho-alveolar macrophages were identified as one source of NGF production. Splenic mononuclear cells from allergen-sensitized mice produced NGF in response to allergen. They responded to exogenously added NGF with a dose-dependent increase in IL-4 and IL-5 production and augmented IgE and IgG1 synthesis. In contrast, IFN- and IgG2a levels remained unaffected. The effects were NGF specific, since they could be blocked by an anti-NGF-antibody. Nasal application of anti-NGF to allergen-sensitized mice significantly reduced IL-4 and prevented development of airway hyperreactivity. These results show that allergic airway inflammation is accompanied by enhanced local NGF production that acts as an amplifier for Th2 effector functions and plays an important role in the development of airway hyperreactivity. Therefore it is suggested that NGF may serve as a link between the immune and nerve system.
Nerve growth factor (NGF) is a well characterized molecule required for the survival and differentiation of a variety of cell types both in the peripheral and central nervous system. Numerous studies published in recent years have demonstrated that NGF affects different functional activities of mature immune and hematopoietic cells. Other studies have revealed that hematopoietic progenitor cells from bone marrow, umbilical cord blood and peripheral blood are receptive to the action of NGF and that bone marrow stromal cells produce/respond to NGF during different steps of normal hematopoiesis. Elevated levels of NGF have been found in a number of inflammatory diseases, including those of autoimmune nature and in myeloproliferative pathologies. This review presents these data and discusses the hypothesis of a possible functional role of NGF in immune and hematopoietic disorders. Copyright © 1999 John Wiley & Sons, Ltd.
The tissue distribution of neurotrophin-3 (NT-3) was investigated in rats at 1 month of age using a newly established, sensitive two-site enzyme immunoassay system for NT-3, as well as the immunocytochemical localization of this protein. The immunoassay for NT-3 enabled us to quantify NT-3 at levels > 3 pg per assay. In the rat brain, NT-3 was detectable only in the olfactory bulb (0.54 ng/g wet weight), cerebellum (0.71 ng/g), septum (0.91 ng/g), and hippocampus (6.3 ng/g). By contrast, NT-3 was widely distributed in peripheral tissues. Appreciable levels of NT-3 were also found in the thymus (31 ng/g), heart (38 ng/g), diaphragm (21 ng/g), liver (45 ng/g), pancreas (892 ng/g), spleen (133 ng/g), kidney (40 ng/g), and adrenal gland (46 ng/g). An antibody specific for NT-3 bound to pyramidal cells in the CA2-CA4 regions of the hippocampus, to A cells in the islets of Langerhans in the pancreas, to unidentified cells in the red pulp of the spleen, to liver cells, and to muscle fibers in the diaphragm from rats at 1 month of age. Molecular masses of NT-3-immunoreactive proteins in the hippocampus and pancreas were 14 and 12 kDa, respectively. Thus, in rats, NT-3 was detected in restricted regions of the brain and in the visceral targets of the nodose ganglia at high concentrations. Our present results suggest that NT-3 not only functions as a classical target-derived neurotrophic factor but also can play other roles.
The aggressive and highly metastatic behavior observed in pancreatic ductal adenocarcinoma (PDAC) may be due to autocrine and/or paracrine interactions (tumor/stromal) involving altered expression of peptide growth factors and their corresponding receptors. The neurotrophin (NT) growth factor family and their cognate receptors have been demonstrated to play a role in the invasiveness, chemotactic behavior and tumor cell survival of both neuronal and non-neuronal cancers. We hypothesized that aberrant expression of the NTs and/or the Trk receptors may contribute to the malignant phenotype of PDAC, specifically tumor cell invasiveness, through autocrine and/or paracrine interactions. In this study, we examined the expression of NTs, Trks and p75NGFR by immunohistochemical and in situ hybridization analyses in both normal (n = 14) and neoplastic pancreas (n = 47) and PDAC-derived cell lines (n = 6). Further, we evaluated the effects of various NTs on the in vitro invasive and chemotactic behavior on 6 human PDAC-derived cell lines in a modified Boyden chamber assay. Brain-derived nerve growth factor (BDNF), NT-3, NT-4/5 and Trks A, B and C exhibited diffuse cytoplasmic and membranous immunostaining patterns in both the ducts and the acini of the exocrine pancreas and the islets of the endocrine pancreas of both normal and PDAC specimens. NT expression was primarily within the stromal compartment of the tumor, while Trk expression was weak or absent. We observed a 68%, 64% and 66% increase in the expression of Trks A, B and C, respectively, in the ductal elements of the PDAC samples examined compared with the normal adjacent tissue. Invasiveness of 4 of 6 PDAC cell lines was significantly inhibited (p < 0.05) when the cells were incubated with 100 ng/ml NT. However, when select cell lines were incubated with lower concentrations of NT-3 and BDNF (0, 1, 5, 25 and 50 ng/ml), invasiveness was significantly stimulated (p < 0.05) through the Matrigel matrix. Collectively, our data suggest the possibility that paracrine and/or autocrine NT-Trk interactions may influence the phenotype (possibly the invasive behavior) of PDAC. Int. J. Cancer 81:417–427, 1999. © 1999 Wiley-Liss, Inc.
Recently, much attention has been paid to the relationship between the nervous and immune systems. The present study was conducted to clarify the role of neurotrophin low affinity receptor (p75N) in allergic airway inflammation and hyper-responsiveness (AHR) in mice by employing p75N gene deficient mice.
Mice were immunized twice by intraperitoneal injections of ovalbumin (OA) at intervals of 12 days. OA was inhaled 10 days after the secondary immunization and repeated three times at 4 days interval. Twenty-four hours after the last inhalation, airway responsiveness to acetylcholine was measured and bronchoalveolar lavage fluid (BALF) was obtained for examining the number of inflammatory cells and the level of cytokines. Serum immunoglobulin was measured as a marker of systemic immune response before the final inhalation.
In wild-type mice, repeated antigen provocation resulted in airway eosinophilia, AHR and elevations in serum IgE and interleukin (IL)-4 and −5 in BALF. In p75N gene deficient mice, none of the above parameters was observed after antigen provocation. The antigen-induced production of interferon (IFN)-γ and nerve growth factor (NGF) were not altered by depletion of p75N gene.
The present findings suggest that p75 gene deficiency disrupt an allergic airway inflammation and AHR in mice by interfering type 2 helper T (Th2) cell responses.
British Journal of Pharmacology (2001) 134, 1580–1586; doi:10.1038/sj.bjp.0704411
A novel pH shock extraction procedure was used to measure nerve growth factor (NGF) levels in both normal and inflamed synovial fluids using a sensitive and specific two-site enzyme linked immunosorbant assay. To date no data is available on NGF levels in normal synovial fluids. Synovial fluids were taken from 5 normal volunteers, 12 patients with rheumatoid arthritis and 10 patients with other inflammatory arthropathies. The mean SEM NGF concentration in normal synovial fluids was 95 33.2 pg/ml (range 39.1–143.1 pg/ml), whereas the mean NGF concentration in the synovial fluids taken from patients with rheumatoid arthritis was 532.5 123.8 pg/ml (range 152–1686 pg/ml). The mean NGF concentration in patients with other inflammatory arthropathies was also raised (430.6 90 pg/ml; range 89–1071 pg/ml). The NGF concentrations were significantly higher in the synovial fluids from both inflamed groups (ANOVA p < 0.05)="" compared="" to="" normals.="" raised="" levels="" of="" ngf="" in="" synovial="" fluid="" may="" contribute="" directly="" to="" joint="" inflammation="" via="" activation="" of="" inflammatory="">
The aim of this work was to study the topographic distribution and the morphological behaviour of nerve growth factor (NGF) primed spleen cells injected into the lateral ventricles of developing rat brain. Serial coronal brain sections showed that these transplanted cells acquire phenotypical characteristics similar to those of mast cells (MCs) and that they enhance local neovascularization. These results, together with the observation that these cells are located in proximity to the hippocampus, a brain tissue which contains one of the highest levels of NGF, provide a model for studying the relationship between NGF and MC differentiation and secretion.
Adrenergic nerve fibers (ANF) were studied in juvenile, adult and old rats by biochemical and morphological methods and by quantitative analysis of images (QAI). After chemical sympathectomy with neurotoxin 6-OH dopamine, the greater part of ANF disappeared. The whole thymus was drawn in juvenile normal or sympathectomized rats, in adult normal or sympathectomized rats and in old normal or sympathectomized rats. Thymuses from the above-mentioned animals were weighed, measured and dissected. Thymic slices were stained with eosin orange for the detection of the microanatomical details and with Bodian’s method for the recognition of the whole nerve fibers. Histofluorescence microscopy was used for staining of ANF while immunofluorescence microscopy was employed for staining of neuropeptide Y (NPY)-like immunoreactivity. Biochemical dosage of proteins and of noradrenaline amount was performed. Finally, all morphological results were subjected to QAI. Our results suggest that: (1) total innervation of the thymus increases with age; (2) ANF do not change with age; (3) the content of noradrenaline in the thymus increases with age; and (4) NPY-like immunoreactive structures in the thymus decrease with age. Biochemical results are in accordance with the morphological ones and both are confirmed by means of QAI. The probable function of sympathetic innervation of rat thymus is also discussed.
We investigated inhibitory activity of nerve growth factor (NGF) on apoptosis of murine peritoneal exudate neutrophils. During culture for 9h, apoptotic cells were identified by morphological changes under a light microscope: nuclear pyknosis and chromatin condensation with or without cytoplasmic vacuolation. The apoptotic state was confirmed by DNA fragmentation indicating the endogenous endonuclease activation. When neutrophils were incubated in the presence of NGF, the proportion of cells with the morphological changes was decreased in a dose-dependent manner, and the development of the characteristic DNA fragmentation was restricted. The apoptosis-suppressing activity of NGF was abolished by the addition of anti-NGF monoclonal antibody. These results suggest that NGF may suppress neutrophil apoptosis by preventing the endogenous endonuclease activation.
The adsorption behavior of pentachlorophenol (PCP) from aqueous solution to activated sludge biomass was quantitatively characterized in this paper. The effects of the initial pH value and biomass concentration on bioadsorption were investigated. The Freundlich adsorption isotherm was applied to describe the biosorption processes and the isotherm constants were evaluated. The experimental results indicated that the initial pH value and biomass concentration are important parameters affecting the adsorption capacity that increased with decreasing biomass concentration (in the range less than 5 g/l) and pH (between 6 and 8). Both the biomass concentration and pH value only affected the capacity constant KF of the Freundlich equation while the intensity constant n remained constant.
Allergic bronchial asthma is characterized by chronic inflammation of the airways, development of airway hyperreactivity and recurrent reversible airway obstruction. Target and effector cells responsible for airway hyperresponsiveness and airway obstruction include sensory and motor neurons as well as epithelial and smooth muscle cells. Although it is well established that the inflammatory process is controlled by T-helper (Th) 2 cells and the Th2-derived cytokines interleukin-4, airway hyperresponsiveness-5 and interleukin-13, the mechanisms by which immune cells interact with neurons, epithelial cells or smooth muscle cells still remain uncertain. Since there is growing evidence for extensive communication between neurons and immune cells, the mechanisms of this neuro-immune crosstalk in lung and airways of asthmatic patients are recently becoming the focus of asthma research. Neurotrophins represent candidate molecules regulating and controlling this crosstalk between the immune and peripheral nervous system. They are constitutively expressed by resident lung cells and produced in increasing concentrations by immune cells invading the airways under pathological conditions. They modify the functional activity of sensory and motor neurons, leading to enhanced and altered neuropeptide and tachykinin production. These effects are defined as “neuronal plasticity”. The consequences are the development of “neurogenic inflammation” due to neuropeptide and tachykinin activities.
Many investigators have reported proliferation of terminal cutaneous nerves and upregulation of various neuropeptides (substance P, vasoactive intestinal polypeptide, calcitonin gene-related peptide) in psoriatic lesions. Nerve growth factor promotes growth of nerves and causes upregulation of neuropeptides like substance P and calcitonin gene-related peptide. In this study we investigated the expression of nerve growth factor in psoriatic lesions, non-lesional psoriatic skin, lichen planus and normal control skin. Immunoperoxidase staining was applied on cryosections prepared from snap-frozen biopsy specimens. The primary antibody used was a polyclonal anti-NGF-beta antibody. Nerve growth factor was detected only in the keratinocytes. In psoriatic tissue the number of keratinocytes per square millimeter of epidermis positive for nerve growth factor was 84.7 +/- 46.3 compared to 44.8 +/- 29.9, 18.9 +/- 11.8 and 7.5 +/- 16.9, respectively, in non-lesional psoriatic skin, normal skin and lichen planus. Increased expression of nerve growth factor substantiates larger numbers of terminal cutaneous nerves and upregulations of substance P and calcitonin gene-related peptide in psoriatic lesions. In addition, nerve growth factor is mitogenic to keratinocytes, activates T-lymphocytes and can induce migration of inflammatory cellular infiltrates, histological features characteristic of psoriasis.
Using neonatal rats we investigated the role of the thymus and thymosin-alpha1 (T-alpha1) in brain NGF levels, NGF receptor (p75NGFr) expression, as well as the activity of choline acetyl-transferase, a cholinergic enzyme regulated by NGF. It is shown that early postnatal thymectomy causes a decrease in NGF in the hippocampus and cortex and p75NGFr distribution in the basal forebrain cholinergic neurons (FBCN). Intracerebral T-alpha1 injection in thymectomized animals induces a recovery, albeit not complete, of both NGF and p75NGFr. These findings indicate that thymectomy affects both the brain NGF producing and responding cells and that T-alpha1 may be one of the thymic hormones involved in the regulation of cerebral NGF synthesis.
Both epidermal growth factor (EGF) and nerve growth factor (NGF) were found to moderate the reactivity of mouse spleen cells in an in vitro model of immune response. Blastogenic response was suppressed by EGF and potentiated by NGF. Both proteins are present in mouse, but not human, saliva in quantities equal to or greater than those affecting blastogenic response in our assay. Immune response occurring in the mouse periodontium may be affected by the presence of these factors in the saliva.
Congenital insensitivity to pain with anhidrosis (CIPA) is characterized by recurrent episodes of unexplained fever, anhidrosis (inability to sweat), absence of reaction to noxious stimuli, self-mutilating behavior, and mental retardation. Human TRKA encodes a high-affinity tyrosine kinase receptor for nerve growth factor (NGF), a member of the neurotrophin family that induces neurite outgrowth and promotes survival of embryonic sensory and sympathetic neurons. We have recently demonstrated that TRKA is responsible for CIPA by identifying three mutations in a region encoding the intracellular tyrosine kinase domain of TRKA in one Ecuadorian and three Japanese families. We have developed a comprehensive strategy to screen for TRKA mutations, on the basis of the gene's structure and organization. Here we report 11 novel mutations, in seven affected families. These are six missense mutations, two frameshift mutations, one nonsense mutation, and two splice-site mutations. Mendelian inheritance of the mutations is confirmed in six families for which parent samples are available. Two mutations are linked, on the same chromosome, to Arg85Ser and to His598Tyr;Gly607Val, hence, they probably represent double and triple mutations. The mutations are distributed in an extracellular domain, involved in NGF binding, as well as the intracellular signal-transduction domain. These data suggest that TRKA defects cause CIPA in various ethnic groups.
In addition to its neurotrophic activity, nerve growth factor (NGF) has been shown to interact with cells of the immune system. We have characterized the effects of NGF on human B cell proliferation and the regulation of NGF receptor expression on these cells. Nerve growth factor receptors were expressed on all tonsillar and peripheral blood B cells and this expression was increased upon activation of the cells. NGF augmented the mitogenic effect of the T-independent B cell mitogen, Staphylococcus aureus Cowan I strain, and provided a progression signal to competent B cells. The proliferative response was augmented when the progression signal provided by NGF was combined with that provided by IL-2 but not with IL-4. One effect of the interaction between NGF and IL-2 appears to occur at the receptor level, because each of these ligands increased the expression of the receptor for the other ligand, whereas IL-4 was without effect. These results demonstrate the expression of functional receptors on human B lymphocytes, the involvement of NGF in immuno-regulation, and indicate that NGF may act as a B cell growth factor.
Nerve growth factor (NGF) has a modulating effect on immune function, which may occur as a consequence of binding to the NGF receptor (NGF-R). To determine if mRNA for the gene coding for p75NGFR (low affinity NGF-R) is present in lymphocytes, Northern blot analysis of mRNA from human peripheral blood lymphocytes (PBL) and purified T lymphocytes was initiated using cDNA probe for human p75NGFR. p75NGFR mRNA was present in PBL and T lymphocytes, and the mRNA in response to phytohemagglutinin stimulation showed maximum levels at 14 hr of stimulation. p75NGFR mRNA content when analyzed in PBL and T cells from volunteers of various ages showed that p75NGFR mRNA expression does not change with the age of the cell donor.
Cytokines regulate nerve growth factor (NGF) synthesis during inflammatory processes. Since cytokines are also involved in the inflammatory processes of autoimmune rheumatic diseases, we examined levels of NGF in patients with rheumatoid or other types of chronic arthritis. NGF was present in the synovial fluid and synovium of patients with chronic arthritis, but was undetectable in control fluids. We conclude that NGF might be involved in the pathogenesis of arthritis.
Tumor necrosis factor (TNF) as well as the hematopoietic growth factors interleukin-3, interleukin-5, and granulocyte-macrophage colony-stimulating factor affect several eosinophil functions. We previously reported (J. Exp. Med. 1989. 170: 467; 1990. 172: 1577) that the hematopoietic growth factors also potentiate leukotriene C4 (LTC4) formation by eosinophils as well as basophils stimulated with soluble chemotactic peptides such as N-formyl-methionyl-leucyl-phenylalanine (FMLP), but whether TNF also modulates lipid mediator generation in normodense eosinophils triggered with FMLP is unknown. Here we show that a short preincubation (10 min) of human eosinophils purified from healthy donors with low concentrations of TNF (5-150 pM) strongly enhances LTC4 formation in response to FMLP. However, basophil mediator release is not affected by TNF preincubation. Nerve growth factor (NGF), the receptor of which is structurally related to the TNF receptors, tended to suppress lipid mediator synthesis in eosinophils, in contrast to its profound potentiating capacity on basophil mediator release. Thus, the present study demonstrates a first difference in susceptibility of eosinophils and basophils towards cytokines, indicating that TNF and NGF may regulate the relative importance of effector functions of these otherwise closely related cell types.
Nerve growth factor (NGF) is a neurotrophic cytokine known to regulate the survival and function of peripheral and central neuronal cells. Recently, the spectrum of action could be extended to non-neuronal cell types such as rat mast cells and human B lymphocytes. The present study shows that NGF affects the function of mature human basophils isolated from the peripheral blood of healthy donors. Both murine NGF 7S and recombinant human NGF beta enhance histamine release and strongly modulate the formation of lipid mediators by basophils in response to various stimuli. This priming effect of NGF on basophils occurs rapidly within 10 to 15 minutes of preincubation, is dose-dependent, and requires similarly low concentrations (1 to 40 pmol/L) of human NGF beta as the induction of neurite outgrowth in ganglion cells. Cell fractionation studies indicate that NGF acts directly on human basophils without an involvement of other cell types, suggesting the presence of high-affinity NGF receptors on basophils. NGF by itself (up to 4 nmol/L of human NGF beta) does not induce the release of inflammatory mediators directly. The effect of human NGF on basophil mediator release is similar to that of the hematopoietic growth factors interleukin-3, interleukin-5, and granulocyte-macrophage colony-stimulating factor. The present study further demonstrates that NGF acts as a pleiotropic cytokine at the interface between the nervous and the immune system, and that NGF may be involved in inflammatory processes and hypersensitivity reactions.
We report the isolation and molecular characterization of trkC, a new member of the trk family of tyrosine protein kinase genes. trkC is preferentially expressed in the brain. In situ hybridization studies revealed trkC transcripts in the hippocampus, cerebral cortex, and the granular cell layer of the cerebellum. The product of the trkC gene has been identified as a glycoprotein of 145,000 daltons, gp145trkC, which is equally related to the previously characterized gp140trk and gp145trkB tyrosine kinases. gp145trkC is a functional receptor for neurotrophin-3 (NT-3). However, gp145trkC does not bind the highly related neurotrophic factors NGF or BDNF. In proliferating cells, the interaction between gp145trkC and NT-3 elicits a more efficient biological response than when NT-3 binds to its other receptors gp140trk and gp145trkB. These results indicate that gp145trkC may play an important role in mediating the neurotrophic effects of NT-3.
Nerve growth factor (NGF) is a neurotropic polypeptide which has broad biological activity other than support of growth and survival of sympathetic, sensory and central neurons. NGF promotes rat mast cell hyperplasia in vivo and human granulopoiesis in vitro, selectively augmenting basophil/mast cell differentiation in the presence of T cells or conditioned medium derived from a human T cell line (Mo-CM), a source of granulocyte-macrophage colony-stimulating factor (GM-CSF). NGF also synergizes with GM-CSF to promote human basophil/mast cell differentiation in both methylcellulose and suspension cultures of myeloid progenitors. In the current studies, we examined the interactions of NGF and several cytokines considered to be involved in human basophil/mast cell and eosinophil growth and differentiation, including interleukin (IL)-3, IL-4, IL-5, GM-CSF and granulocyte colony-stimulating factor (G-CSF). NGF synergistically enhanced IL-5 induced dose-dependent increases in histamine content and basophilic cell differentiation of myeloid leukemic HL-60 cells, but was only additive to similar effects of IL-3. In contrast, IL-4 and G-CSF did not promote basophilic differentiation of HL-60 cells in the presence or absence of NGF. Various combinations of GM-CSF, G-CSF, IL-3, IL-4 and IL-5 could not reproduce the synergy observed between NGF and either IL-5 or GM-CSF. NGF appears to represent a class of lineage-specific co-factors, in this case being involved in GM-CSF- or IL-5-induced basophilic lineage differentiation, thus contributing to tissue inflammation or repair.
Nerve growth factor (NGF) is a neurotrophic factor responsible for the differentiation and survival of sympathetic and sensory neurons as well as selective populations of cholinergic neurons. NGF binds to specific cell-surface receptors but the mechanism for transduction of the neurotrophic signal is unknown. Several experiments using the NGF-responsive pheochromocytoma cell line, PC12, have implicated tyrosine phosphorylation in NGF-mediated responses, although no NGF-specific tyrosine kinases have been identified. Here we show that NGF induces tyrosine phosphorylation and tyrosine kinase activity of the trk proto-oncogene product, a tyrosine kinase receptor whose expression is restricted in vivo to neurons of the sensory spinal and cranial ganglia of neural crest origin. Tyrosine phosphorylation of trk by NGF is rapid, specific and occurs with picomolar quantities of factor, indicating that the response is mediated by physiological amounts of NGF. Activation of the trk tyrosine kinase receptor provides a possible mechanism for signal transduction by NGF.