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Functional Plasticity of Macrophages: Reversible Adaptation to Changing Microenvironments
Abstract
There has been substantial research activity in the past decade directed at phenotyping macrophage lineages and defining macrophage functional subsets or patterns of activity. The emphasis over the past 2-3 years has been to divide macrophage functional patterns into type 1 (Th1-driven) or type 2 (Th2-driven) functions. However, a huge array of environmental factors (including cytokines, chemokines, pattern recognition receptors, hormones) differentially regulates macrophage response patterns, resulting in the display of numerous distinct, functional phenotypes. Upon stimulation, a macrophage does not display just a single set of functions but rather displays a progression of functional changes in response to the progressive changes in its microenvironment. The remarkable ability of monocytes and tissue macrophages to adapt to changes in their microenvironment challenges the thesis that macrophages displaying unique tissue-specific or response-specific, functional patterns represent distinct lineages. With the exception of mature osteoclasts and mature dendritic cells, evidence supporting stable differentiation as the basis for macrophage functional heterogeneity is equivocal. The concept of whether macrophages develop into functional subsets as opposed to continuously adapting their functional pattern in response to the changing environment of a progressive inflammatory response is important to resolve from the perspectives of therapeutic targeting and understanding the role of macrophages in disease pathogenesis.
... Ce sont en effet des cellules effectrices spécialisées dans la destruction des microorganismes. Elles sont généralement induites par des cytokines Th1, telles que l'IFN-γ et le TNF-α, ou par reconnaissance d'agoniste de Toll-like récepteurs (TLRs) tel que le lipopolysaccharides bactériens (LPS) (Gordon and Taylor, 2005;Stout and Suttles, 2004). ...
... Cependant, un excès de production de FRO par les M1 conduit à l'endommagement des tissus et altère la régénération des tissus et la cicatrisation des plaies. Pour empêcher ces effets délétères, la réponse inflammatoire médiée par les M1 est inhibée via les mécanismes anti-inflammatoires des macrophages M2 (Stout and Suttles, 2004). ...
L'interleukine-10 (IL-10) est une puissante cytokine anti-inflammatoire produite par la plupart des cellules de l'immunité innée et adaptative et dont les monocytes en sont une cible majeure. La liaison de l'interleukine-10 à son récepteur initie une signalisation intracellulaire impliquant STAT3 ce qui induit l'expression de gènes codant pour des facteurs anti-inflammatoires. Du fait de son action immuno-modulatrice, l'IL-10 a été considérée comme un outil thérapeutique intéressant dans les maladies les maladies inflammatoires aigües ou chroniques, et les maladies auto-immunes ayant une composante inflammatoire. Cependant l'administration de l'IL-10 n'a montré que peu d'efficacité dans diverses situations pathologiques telle que la polyarthrite rhumatoïde (PR). La difficulté pourrait être liée à la complexité du foyer inflammatoire où la présence de multiples cytokines pourrait affecter la signalisation de l'IL-10. Dans ce contexte l'objectif de la thèse était de déterminer si le TNFα, une cytokine pro-inflammatoire majeure, pouvait altérer la signalisation de l'interleukine-10 dans les monocytes humains et de déterminer mécanismes sous-jacents, impliquant la NADPH oxydase 2 (NOX2) acteur important de la signalisation cellulaire et dont le TNFα en est agoniste, ainsi que l'impact potentiel dans les situations inflammatoires pathologiques, telle que la PR, en utilisant un modèle expérimental murin. Nos résultats montrent que le TNFα interfère avec la signalisation de l'IL-10 en induisant une déphosphorylation rapide de STAT3 dans les monocytes humains. La déphosphorylation de STAT3 induite par le TNFα se traduit par une diminution de la capacité de l'IL-10 à induire l'expression de SOCS3 un facteur anti-inflammatoire majeur. La diminution de la phosphorylation de STAT3 impliquait une phosphatase SHP1 / 2 car l'utilisation du NSC-87877, un inhibiteur de SHP1 / 2, empêche l'action inhibitrice du TNFα sur la signalisation de l'IL-10. Dans les monocytes stimulés par le TNFα la SHP1 est activée alors que la SHP2 ne l'est pas, suggérant l'implication de SHP1 et non pas celle de SHP2 dans la déphosphorylation de STAT3. L'activation de SHP1 par le TNFα est dépendante de NOX2 car nous avons observé que le diphénylèneiodonium, un inhibiteur de NOX2, supprime l'activation de SHP1 et la déphosphorylation de STAT3 déclenchée par le TNFα. De plus, H2O2 a reproduit l'action inhibitrice du TNFα sur la signalisation de l'IL-10. Par ailleurs, l'activation de SHP1 par les FRO dans les monocytes stimulés par le TNFα est médié par la tyrosine kinase Lyn connue pour être régulée par oxydation. Enfin, l'inhibiteur SHP1/2, NSC-87877, a atténue l'arthrite induite par les anticorps de collagène (CAIA) chez la souris. Ces résultats révèlent que le TNFα perturbe la signalisation de l'IL-10 en induisant la déphosphorylation de STAT3 via l'axe NOX2-ROS-Lyn-SHP1 dans les monocytes humains et que l'inhibition de SHP1/2 in vivo protège contre la CAIA. Cette nouvelle découverte pourrait expliquer la résistance à l'IL-10 dans l'arthrite et pourrait être utile pour exploiter l'IL-10 dans l'immunothérapie.
... Although Th1 and Th2 cells can secrete cytokines in certain contexts that influence the polarization of M1 and M2 macrophages, respectively, they are not the only factor that determines polarization, as shown in this study, where the predominant phenotype was M1 after treatment with both argentatins irrespective of the low differentiation capacity for Th1 cells [38]. ...
Argentatins are secondary metabolites synthesized by guayule (Parthenium argentatum A. Gray) with numerous potential medical applications. In addition to inhibiting insect growth, they are endowed with several pharmacological properties including antimicrobial and antitumorigenic activity. However, their potential as immunomodulators remains unexplored. The aim of the present study was to investigate whether argentatins can modulate the function of the immune system. Human mesenchymal stem cells were treated with argentatins and the production of several anti- and proinflammatory cytokines was evaluated. The effect of argentatins on the polarization of CD4+ T-lymphocytes and macrophages was also assessed. Results demonstrated that argentatins can modulate the production of proinflammatory cytokines and the polarization of cellular phenotypes, including Th2 lymphocytes and M1 macrophages. These findings suggest that argentatins are promising therapeutic agents in autoimmune or allergic diseases, and open new perspectives for the investigation of argentatins in immune response and in the development of more targeted and effective immunomodulatory therapies.
... The role of macrophages in MAS has been widely recognized as these cells may be responsible for hemophagocytosis. These cells, on the other hand, also play a critical role in the regulation of the excessive immune response [15] due to their functional plasticity in response to various stimuli in the inflammatory microenvironment [16]. It has been suggested that the pro-inflammatory M1 and anti-inflammatory M2 phenotypes of macrophages may be two ends of a continuous spectrum of various intermediate phenotypes, finely regulated in response to external stimuli [17,18]. ...
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition characterized by the uncontrolled activation of cytotoxic T lymphocytes, NK cells, and macrophages, resulting in an overproduction of pro-inflammatory cytokines. A primary and a secondary form are distinguished depending on whether or not it is associated with hematologic, infectious, or immune-mediated disease. Clinical manifestations include fever, splenomegaly, neurological changes, coagulopathy, hepatic dysfunction, cytopenia, hypertriglyceridemia, hyperferritinemia, and hemophagocytosis. In adults, therapy, although aggressive, is often unsuccessful. We report the case of a 41-year-old man with no apparent history of previous disease and an acute onset characterized by fever, fatigue, and weight loss. The man was from Burkina Faso and had made trips to his home country in the previous five months. On admission, leukopenia, thrombocytopenia, increased creatinine and transaminases, LDH, and CRP with a normal ESR were found. The patient also presented with hypertriglyceridemia and hyperferritinemia. An infectious or autoimmune etiology was ruled out. A total body CT scan showed bilateral pleural effusion and hilar mesenterial, abdominal, and paratracheal lymphadenopathy. Lymphoproliferative disease with HLH complication was therefore suspected. High doses of glucocorticoids were then administered. A cytologic analysis of the pleural effusion showed anaplastic lymphoma cells and bone marrow aspirate showed hemophagocytosis. An Epstein–Barr Virus (EBV) DNA load of more than 90000 copies/mL was found. Bone marrow biopsy showed a marrow localization of peripheral T lymphoma. The course was rapidly progressive until the patient died. HLH is a rare but usually fatal complication in adults of hematologic, autoimmune, and malignant diseases. Very early diagnosis and treatment are critical but not always sufficient to save patients.
... The heterogeneity in behaviour may be the consequence of a wide range of environmental factors, including cytokines, chemokines, pattern recognition receptors, hormones, and others, differentially regulating the response [30]. Given the stimulative, progressive changes in the microenvironment, which were both in vitro as well as in vivo, the functional response can be dynamic in nature and may change over time [31]. Studies suggest that macrophages can be re-stimulated by the present cytokine milieu and perform a functional shift [32]. ...
Different studies suggest an impact of biofilms on carcinogenic lesion formation in varying human tissues. However, the mechanisms of cancer formation are difficult to examine in vivo as well as in vitro. Cell culture approaches, in most cases, are unable to keep a bacterial steady state without any overgrowth. In our approach, we aimed to develop an immunocompetent 3D tissue model which can mitigate bacterial outgrowth. We established a three-dimensional (3D) co-culture of human primary fibroblasts with pre-differentiated THP-1-derived macrophages on an SIS-muc scaffold which was derived by decellularisation of a porcine intestine. After establishment, we exposed the tissue models to define the biofilms of the Pseudomonas spec. and Staphylococcus spec. cultivated on implant mesh material. After 3 days of incubation, the cell culture medium in models with M0 and M2 pre-differentiated macrophages presented a noticeable turbidity, while models with M1 macrophages presented no noticeable bacterial growth. These results were validated by optical density measurements and a streak test. Immunohistology and immunofluorescent staining of the tissue presented a positive impact of the M1 macrophages on the structural integrity of the tissue model. Furthermore, multiplex ELISA highlighted the increased release of inflammatory cytokines for all the three model types, suggesting the immunocompetence of the developed model. Overall, in this proof-of-principle study, we were able to mitigate bacterial overgrowth and prepared a first step for the development of more complex 3D tissue models to understand the impact of biofilms on carcinogenic lesion formation.
... Intercellular communications between liver cells are complex and dependent on the microenvironmental state. Cell response to metabolic or immune stimuli will change over time depending on the type of signal released, the gene expression, and the duration of the inflammatory event [18]. Several types of liver cells are implicated in the complex process involved in the development of NAFLD and subsequent progression to NASH. ...
Non-coding RNAs (ncRNAs) are RNA molecules that do not code for protein but play key roles in regulating cellular processes. NcRNAs globally affect gene expression in diverse physiological and pathological contexts. Functionally important ncRNAs act in chromatin modifications, in mRNA stabilization and translation, and in regulation of various signaling pathways. Non-alcoholic fatty liver disease (NAFLD) is a set of conditions caused by the accumulation of triacylglycerol in the liver. Studies of ncRNA in NAFLD are limited but have demonstrated that ncRNAs play a critical role in the pathogenesis of NAFLD. In this review, we summarize NAFLD’s pathogenesis and clinical features, discuss current treatment options, and review the involvement of ncRNAs as regulatory molecules in NAFLD and its progression to non-alcoholic steatohepatitis (NASH). In addition, we highlight signaling pathways dysregulated in NAFLD and review their crosstalk with ncRNAs. Having a thorough understanding of the disease process’s molecular mechanisms will facilitate development of highly effective diagnostic and therapeutic treatments. Such insights can also inform preventive strategies to minimize the disease’s future development.
... Recently, it has been demonstrated that IL-1α, IL-13, TNF-α, and IFN-γ secreted by T cells are sufficient to promote SCs' expansion both in vivo and in vitro [64]. Differentiation of SCs and maturation of newly formed myofibres is supported by the switch to an anti-inflammatory microenvironment promoted by M2 macrophages [65]. M2 macrophages produce anti-inflammatory cytokines, including IL-4, IL-10, and IL-13, to suppress the local inflammatory response at the injury site [66]. ...
Skeletal muscle regeneration is a complex process involving the generation of new myofibers after trauma, competitive physical activity, or disease. In this context, adult skeletal muscle stem cells, also known as satellite cells (SCs), play a crucial role in regulating muscle tissue homeostasis and activating regeneration. Alterations in their number or function have been associated with various pathological conditions. The main factors involved in the dysregulation of SCs’ activity are inflammation, oxidative stress, and fibrosis. This review critically summarizes the current knowledge on the role of SCs in skeletal muscle regeneration. It examines the changes in the activity of SCs in three of the most common and severe muscle disorders: sarcopenia, muscular dystrophy, and cancer cachexia. Understanding the molecular mechanisms involved in their dysregulations is essential for improving current treatments, such as exercise, and developing personalized approaches to reactivate SCs.
... A switch is possible from M2 to M1, thanks to the plasticity of these macrophages, by changes in the characteristics of the TME [39]. The inhibition of cathepsins B, S and L may induce a repolarization from M2 towards an M1-like phenotype with an increased expression of several typical M1 mediators, including IL-1, IL-6, CCL2, TNFA, NOS2, NFkBp65, CCR7, and FASN in the repolarized macrophages [40]. ...
Background/Objective
Tumor-associated macrophages (TAMs) produce an excessive amount of cysteine proteases, and we aimed to study the effects of anticancer rhenium(I)-diselenoether (Re-diSe) on the production of cathepsins B and S by macrophages. We investigated the effect of Re-diSe on lipopolysaccharides (LPS) induced M1 macrophages, or by interleukin 6 (IL-6) induced M2 macrophages.
Methods
Non-stimulated or prestimulated murine Raw 264 or human THP-1 macrophages were exposed to increasing concentrations of the drug (5, 10, 20, 50 and 100 μM) and viability was assayed by the MTT assay. The amount of cysteine proteases was evaluated by ELISA tests, the number of M1 and M2 macrophages by the expression of CD80 or CD206 biomarkers. The binding of Re-diSe with GSH as a model thiol-containing protein was studied by mass spectrometry.
Results
A dose-dependent decrease in cathepsins B and S was observed in M1 macrophages. There was no effect in non-stimulated cells. The drug induced a dramatic dose-dependent increase in M1 expression in both cells, significantly decreased the M2 expression in Raw 264 and had no effect in non-stimulated macrophages. The binding of the Re atom with the thiols was clearly demonstrated.
Conclusion
The increase in the number of M1 and a decrease in M2 macrophages treated by Re-diSe could be related to the decrease in cysteine proteases upon binding of their thiol residues with the Re atom.
... In recent years, several studies have focused on the subtypes and adaptability of monocytes/macrophages. Macrophages are mainly divided into two phenotypes based on their function: M1 and M2 (Stout and Suttles, 2004). During the early stage of inflammation, activated M1 macrophages release TNFα and IL12, while M2 macrophages stimulate IL10 production to play an antiinflammatory role during the resolution phase (Almubarak et al., 2020). ...
Periodontitis, a condition that results in periodontal attachment loss and alveolar bone resorption, contributes to the global burden of oral disease. The underlying mechanism of periodontitis involves the dysbiosis and dyshomeostasis between host and oral microbes, among which the macrophage is one of the major innate immune cell players, producing interferon β (IFNβ) in response to bacterial infection. The objective of this research was to examine the interaction of macrophages with periodontitis and the role and mechanism of IFNβ on macrophages. IFNβ has been shown to have the potential to induce the differentiation of M1 to M2 macrophages, which are stimulated by low levels of lipopolysaccharide (LPS). Additionally, IFNβ has been demonstrated to promote the production of ISG15 by macrophages, which leads to the inhibition of the innate immune response. Moreover, our investigation revealed that IFNβ has the potential to augment the secretion of ISG15 and its downstream cytokine, IL10, in LPS-stimulated macrophages. Single-cell analysis was conducted on the gingival tissues of patients with periodontitis, which revealed a higher proportion of macrophages in the periodontitis-diseased tissue and increased expression of IFNβ, ISG15, and IL10. Gene Set Enrichment Analysis indicated that bacterial infection was associated with upregulation of IFNβ, ISG15, and IL10. Notably, only IL10 has been linked to immunosuppression, indicating that the IFNβ-ISG15-IL10 axis might promote an anti-inflammatory response in periodontitis through IL10 expression. It is also found that macrophage phenotype transitions in periodontitis involve the release of higher levels of IFNβ, ISG15, and IL10 by the anti-inflammatory M2 macrophage phenotype compared to the pro-inflammatory M1 phenotype and myeloid-derived suppressor cells (MDSCs). This implies that the IFNβ-induced production of IL10 might be linked to the M2 macrophage phenotype. Furthermore, cell communication analysis demonstrated that IL10 can promote fibroblast proliferation in periodontal tissues via STAT3 signaling.
... Macrophages display highly tumor environment-dependent plasticity that varies their biological function. Macrophages in the TME can be polarized into opposite functional states, known as M1 and M2 polarization [71][72][73]. M1 and M2 are classified as highly simplified models of complex functional behavior and cellular plasticity. The M1 phenotype is characterized by the expression of high levels of proinflammatory cytokines, high production of reactive nitrogen and oxygen intermediates, promotion of the Th1 response, and strong microbicidal and tumoricidal activity. ...
Adenosine, an immunosuppressive metabolite, is produced by adenosine triphosphate (ATP) released from dying or stressed cells and is found at high levels in the tumor microenvironment of most solid tumors. It mediates pro-tumor activities by inducing tumor cell proliferation, migration or invasion, tumor tissue angiogenesis, and chemoresistance. In addition, adenosine plays an important role in regulating anti-tumor immune responses and facilitating tumor immune escape. Adenosine receptors are broadly expressed by tumor-infiltrated immune cells, including suppressive tumor-associated macrophages and CD4+ regulatory T cells, as well as effector CD4+ T cells and CD8+ cytotoxic T lymphocytes. Therefore, adenosine is indispensable in down-regulating anti-tumor immune responses in the tumor microenvironment and contributes to tumor progression. This review describes the current progress on the role of adenosine/adenosine receptor pathway in regulating the tumor-infiltrating immune cells that contribute to tumor immune evasion and aims to provide insights into adenosine-targeted tumor immunotherapy.
... Indeed, in addition to regulating and reducing the inflammatory environment, muscle Treg cells play an important role in regeneration through amphiregulin secretion [37,38]. The change of inflammatory environment is mainly based on the change of macrophage populations from pro-inflammatory to anti-inflammatory, under the influence of Th2 and Treg cell cytokines [39]. These macrophages produce anti-inflammatory cytokines (IL-4, IL-10 and IL-13), which reduce the local inflammation induced by the lesion and stimulate the differentiation and fusion of myoblasts into myotubes, promoting the late stage of myogenesis [35,40]. ...
Muscle regeneration is a physiological process that converts satellite cells into mature myotubes under the influence of an inflammatory environment progressively replaced by an anti-inflammatory environment, with precise crosstalk between immune and muscular cells. If the succession of these phases is disturbed, the immune system can sometimes become auto-reactive, leading to chronic muscular inflammatory diseases, such as myositis. The triggers of these autoimmune myopathies remain mostly unknown, but the main mechanisms of pathogenesis are partially understood. They involve chronic inflammation, which could be associated with an auto-reactive immune response, and gradually with a decrease in the regenerative capacities of the muscle, leading to its degeneration, fibrosis and vascular architecture deterioration. Immunosuppressive treatments can block the first part of the process, but sometimes muscle remains weakened, or even still deteriorates, due to the exhaustion of its capacities. For patients refractory to immunosuppressive therapies, mesenchymal stem cells have shown interesting effects but their use is limited by their availability. Stromal vascular fraction, which can easily be extracted from adipose tissue, has shown good tolerance and possible therapeutic benefits in several degenerative and autoimmune diseases. However, despite the increasing use of stromal vascular fraction, the therapeutically active components within this heterogeneous cellular product are ill-defined and the mechanisms by which this therapy might be active remain insufficiently understood. We review herein the current knowledge on the mechanisms of action of stromal vascular fraction and hypothesise on how it could potentially respond to some of the unmet treatment needs of refractory myositis. Cell Death Discovery (2023) 9:346 ; https://doi.
... The first step was to examine whether SP compound 6e has an impact on cell viability. Bone-marrow-derived macrophages are progenitors that are able to differentiate into pro-inflammatory M1 and anti-inflammatory M2 phenotypes, which ideally fit to demonstrate the functional activity of labelled cells in routine biological studies [65][66][67][68][69]. To assess toxicity, the BMDMs were stained with various concentrations (0.1-100 µM) of compound 6e, and after 24 h, cell viability was measured using the CCK-8 assay ( Figure 5). ...
A set of styrylpyridinium (SP) compounds was synthesised in order to study their spectroscopic and cell labelling properties. The compounds comprised different electron donating parts (julolidine, p-dimethylaminophenyl, p-methoxyphenyl, 3,4,5-trimethoxyphenyl), conjugated linkers (vinyl, divinyl), and an electron-withdrawing N-alkylpyridinium part. Geminal or bis-compounds incorporating two styrylpyridinium (bis-SP) moieties at the 1,3-trimethylene unit were synthesised. Compounds comprising a divinyl linker and powerful electron-donating julolidine donor parts possessed intensive fluorescence in the near-infrared region (maximum at ~760 nm). The compounds had rather high cytotoxicity towards the cancerous cell lines HT-1080 and MH-22A; at the same time, basal cytotoxicity towards the NIH3T3 fibroblast cell line ranged from toxic to harmful. SP compound 6e had IC50 values of 1.0 ± 0.03 µg/mL to the cell line HT-1080 and 0.4 µg/mL to MH-22A; however, the basal toxicity LD50 was 477 mg/kg (harmful). The compounds showed large Stokes’ shifts, including 195 nm for 6a,b, 240 nm for 6e, and 325 and 352 nm for 6d and 6c, respectively. The highest photoluminescence quantum yield (PLQY) values were observed for 6a,b, which were 15.1 and 12.2%, respectively. The PLQY values for the SP derivatives 6d,e (those with a julolidinyl moiety) were 0.5 and 0.7%, respectively. Cell staining with compound 6e revealed a strong fluorescent signal localised in the cell cytoplasm, whereas the cell nuclei were not stained. SP compound 6e possessed self-assembling properties and formed liposomes with an average diameter of 118 nm. The obtained novel data on near-infrared fluorescent probes could be useful for the development of biocompatible dyes for biomedical applications.
... Arg1 produces urea and L-ornithine from L-arginine, while iNOS converts the latter into Lcitrulline, producing nitric oxide (NO) [103]. Macrophages are part of the innate immune system and respond to invading bacteria, viruses, fungi, and even cancer cells, changing their phenotype [104]. The two main phenotypes are classically activated macrophages (M1) and alternatively activated macrophages (M2) [105]. ...
Amino acids have been extensively studied in nutrition, mainly as key elements for maintaining optimal protein synthesis in the body as well as precursors of various nitrogen-containing compounds. However, it is now known that amino acid catabolism is an important element for the metabolic control of different biological processes, although it is still a developing field to have a deeper understanding of its biological implications. The mechanisms involved in the regulation of amino acid catabolism now include the contribution of the gut microbiota to amino acid oxidation and metabolite generation in the intestine, the molecular mechanisms of transcriptional control, and the participation of specific miRNAs involved in the regulation of amino acid degrading enzymes. In addition, molecules derived from amino acid catabolism play a role in metabolism as they are used in the epigenetic regulation of many genes. Thus, this review aims to examine the mechanisms of amino acid catabolism and to support the idea that this process is associated with the immune response, abnormalities during obesity, in particular insulin resistance, and the regulation of thermogenesis.
... The induction of pro-inflammatory cytokines and metabolic markers (Arg1) may be the result of cellular overstimulation during reprogramming. On the other hand, as macrophages possess high plasticity, we suppose that they might lose phenotype features when the activation factors are removed [30,31]. Thus, (w/o) control macrophages had lower levels of secreted cytokines, except for IL-1β. ...
Reprogramming of tumor-associated macrophages (TAMs) is a promising strategy for cancer immunotherapy. Several studies have shown that cancer cells induce/support the formation of immunosuppressive TAMs phenotypes. However, the specific factors that orchestrate this immunosuppressive process are unknown or poorly studied. In vivo studies are expensive, complex, and ethically constrained. Therefore, 3D cell interaction models could become a unique framework for the identification of important TAMs programming factors. In this study, we have established and characterized a new in vitro 3D model for macrophage programming in the presence of cancer cell spheroids. First, it was demonstrated that the profile of cytokines, chemokines, and surface markers of 3D-cultured macrophages did not differ conceptually from monolayer-cultured M1 and M2-programmed macrophages. Second, the possibility of reprogramming macrophages in 3D conditions was investigated. In total, the dynamic changes in 6 surface markers, 11 cytokines, and 22 chemokines were analyzed upon macrophage programming (M1 and M2) and reprogramming (M1→M2 and M2→M1). According to the findings, the reprogramming resulted in a mixed macrophage phenotype that expressed both immunosuppressive and anti-cancer immunostimulatory features. Third, cancer cell spheroids were shown to stimulate the production of immunosuppressive M2 markers as well as pro-tumor cytokines and chemokines. In summary, the newly developed 3D model of cancer cell spheroid/macrophage co-culture under free-floating conditions can be used for studies on macrophage plasticity and for the development of targeted cancer immunotherapy.
... Under physiological conditions, most macrophages demonstrate the M2 phenotype, which helps maintain tissue homeostasis [19]. Both resident M2 and inflammatory M1 macrophages can affect bone formation. ...
Maxillary sinus augmentation is a commonly used procedure for the placement of dental implants. However, the use of natural and synthetic materials in this procedure has resulted in postoperative complications ranging from 12% to 38%. To address this issue, we developed a novel calcium deficient HA/β-TCP bone grafting nanomaterial using a two-step synthesis method with appropriate structural and chemical parameters for sinus lifting applications. We demonstrated that our nanomaterial exhibits high biocompatibility, enhances cell proliferation, and stimulates collagen expression. Furthermore, the degradation of β-TCP in our nanomaterial promotes blood clot formation, which supports cell aggregation and new bone growth. In a clinical trial involving eight cases, we observed the formation of compact bone tissue 8 months after the operation, allowing for the successful installation of dental implants without any early postoperative complications. Our results suggest that our novel bone grafting nanomaterial has the potential to improve the success rate of maxillary sinus augmentation procedures.
... Polarization bias of macrophages is influenced by cytokine production, secreted cell byproducts, and extracellular expression of receptors. Macrophage phenotypes are broadly classified as either classical (M1) or alternative (M2), with each type having specific functions during the immune response [81,[85][86][87]. In addition, the macrophage phenotype is plastic and can change with the local cytokine microenvironment [82,88]. ...
Cryptococcus neoformans is an opportunistic fungal pathogen that causes over 180,000 annual deaths in HIV/AIDS patients. Innate phagocytes in the lungs, such as dendritic cells (DCs) and macrophages, are the first cells to interact with the pathogen. Neutrophils, another innate phagocyte, are recruited to the lungs during cryptococcal infection. These innate cells are involved in early detection of C. neoformans, as well as the removal and clearance of cryptococcal infections. However, C. neoformans has developed ways to interfere with these processes, allowing for the evasion of the host’s innate immune system. Additionally, the innate immune cells have the ability to aid in cryptococcal pathogenesis. This review discusses recent literature on the interactions of innate pulmonary phagocytes with C. neoformans.
... Macrophages and monocytes are major drivers of atherosclerosis [7,8] and IHD injury repair [9,10]. They are plastic cells that adapt to their environment [11], which may well differ between males and females. This has prompted several groups to study sex-specific differences in macrophages and monocytes [12][13][14], showing differences in monocyte number [15,16] or inflammatory response [17]. ...
Background and aims:
This study aims to identify sex-specific transcriptional differences and signaling pathways in circulating monocytes contributing to cardiovascular disease.
Methods and results:
We generated sex-biased gene expression signatures by comparing male versus female monocytes of coronary artery disease (CAD) patients (n = 450) from the Center for Translational Molecular Medicine-Circulating Cells Cohort. Gene set enrichment analysis demonstrated that monocytes from female CAD patients carry stronger chemotaxis and migratory signature than those from males. We then inferred cytokine signaling activities based on CytoSig database of 51 cytokine and growth factor regulation profiles. Monocytes from females feature a higher activation level of EGF, IFN1, VEGF, GM-CSF, and CD40L pathways, whereas IL-4, INS, and HMGB1 signaling was seen to be more activated in males. These sex differences were not observed in healthy subjects, as shown for an independent monocyte cohort of healthy subjects (GSE56034, n = 485). More pronounced GM-CSF signaling in monocytes of female CAD patients was confirmed by the significant enrichment of GM-CSF-activated monocyte signature in females. As we show these effects were not due to increased plasma levels of the corresponding ligands, sex-intrinsic differences in monocyte signaling regulation are suggested. Consistently, regulatory network analysis revealed jun-B as a shared transcription factor activated in all female-specific pathways except IFN1 but suppressed in male-activated IL-4.
Conclusions:
We observed overt CAD-specific sex differences in monocyte transcriptional profiles and cytokine- or growth factor-induced responses, which provide insights into underlying mechanisms of sex differences in CVD.
... Elevated levels of reactive oxygen species (ROS) (including O 2 ⋅-, H 2 O 2 , ⋅OH, and 1 O 2 ) in RA joints incessantly lead to increased oxidative stress (protein oxidation, lipid peroxidation, and DNA damage) and intra-articular hypoxia that activate the high expression of several redox-sensitive transcription factors like hypoxia-inducible factor-1 (HIF-1α) [12,13]. Such local adverse microenvironment is reported to induce tendentious M1-subtype polarization of macrophages, and in turn cause synovial inflammation [14,15]. Thus, inhibition of hypoxia, down-regulation of ROS production, and phenotypic transition regulation of macrophage subtype (from M1 to M2) may be promising strategies to ameliorate inflammatory responses and relieve RA [16,17]. ...
Rheumatoid arthritis (RA) is a common chronic disease dominated by inflammatory synovitis, which is characterized with hyperplastic synovium, up-regulated matrix metalloproteinase (MMP) expression, hypoxic joint cavity and excessive reactive oxygen species (ROS) accumulation. Such local adverse microenvironment in RA joints further exacerbates the infiltration of synovial inflammatory cells, especially M1-type macrophages. Regulating intra-articular pathological conditions, eliminating excess M1 macrophages or converting them to an anti-inflammatory M2 phenotype may break the vicious progression circle. Herein, we develop a multi-stimulus responsive lipogel as effective platform to relieve RA symptoms and promote articular cartilage recovery via reversing its inflammatory microenvironment. The injectable lipogel is fabricated by loading polydopamine nanoparticles and methotrexate into a thermosensitive gel, and intra-articularly injected to form the therapeutic depot (PDA/MTX@TSG) in situ. The gel degrades slowly under esterase hydrolysis, and maintains sustained drug release in physiological conditions. Meanwhile, it can 1) induce a reversible gel-sol phase transition upon mild photothermal treatment (external NIR light control), and 2) specifically respond to MMP-rich RA microenvironment (internal enzymatic hydrolysis effect). Such stimulus-responsive system can deliver therapeutic components in a controllable manner, and significantly reverse adverse inflammatory microenvironment of RA joints through ROS eliminating, hypoxia alleviating, and M1-M2 macrophage polarization effects. Animal experiments indicate that observable RA relief and joint repair are realized after a single lipogel injection combined with NIR irradiation. Our study highlights the importance of altering local RA microenvironment via anti-inflammatory macrophage polarization, and therefore presents a potent therapeutic strategy for RA treatment in clinical intervention.
... Angiogenesis is a critical part of tumor growth and progression in general [12] and previous reports indirectly suggest elevated angiogenesis in ACC [13,14], whereas a similar immmunohistological study did not show any significant difference between intratumoral and peritumoral vascularization [15]. Macrophages are a heterogenous group of cells that polarise to a M1 or M2 phenotype and are able to retain their plasticity and transform according to environmental signals [16][17][18]. M2-polarized macrophages, which have been linked to angiogenesis and cancer growth in pancreas [19], are also strongly represented in ACC [20,21] and perhaps, at least partially, responsible for enhanced angiogenesis in this cancer. Till Dato no study to our knowledge compared both aspects. ...
Background
Adenoid cystic carcinoma (ACC) is a rare type of cancer commonly occurring in salivary glands. It is characterized by slow but infiltrative growth, nerve infiltration and overall poor prognosis, with late recurrence and distant metastasis. The treatment of ACC is still limited to surgery and/or (adjuvant) radiotherapy. Till now no promising systemic therapy option exists. However, various studies deliver promising results after treatment with anti-angiogenetic agents, such as anti-EGFR-antibody Cetuximab or Tyrosinkinase inhibitor Lenvatinib.
Methods
By using of immunohistological methods we analyzed and compared the macrophage and lymphocyte populations, vascularization, and PD-L1-status in 12 ACC of the salivary glands.
Results
All cases showed a significant elevation of macrophages with M2 polarization and a higher vascularization in ACC compared to normal salivary gland tissue. The CD4/CD8 quotient was heterogenous. ACC does not show relevant PD-L1 expression.
Conclusions
The predominant M2 polarization of macrophages in ACC could be responsible for elevated vascularization, as already been proved in other cancer types, that M2 macrophages promote angiogenesis.
... Inhibition of these enzymes in immune cells of the tumor microenvironment (TME), dendritic cells, B-and T-cells, and macrophages, may result in an improvement of cell immunity. For example, inhibition of cathepsins B and S could induce a shift from the M2 macrophage phenotype to M1-like phenotype (22), counteracting the immunosuppressive effects of cancer (23). However, cathepsins must be strictly regulated as they are also essential for an optimal immune function (24). ...
Background/aim:
Rhenium(I)-diselenoether (Re-diSe) is a compound combining a rhenium tricarbonyl(I) core with a diselenide ligand. A high dose of 60 mg/kg had a pro-tumor effect in a previous study, in non-immune deficient 4T1 tumor-bearing mice, while doses of 1 and 10 mg/kg did not affect tumor growth, after repeated oral administrations. This study aimed to examine the tumor effects of a lower dose of 0.1 mg/kg with the same experimental design and to assay plasma Re and Se concentrations.
Materials and methods:
Syngenic BALB/cByJ (JAX) mice were orthotopically inoculated with 4T1 mammary breast cancer cells. Re-diSe was daily administered orally for 23 days at doses of 0.1, 1, and 10 mg/kg, whereas controls received no treatment. Tumor and mice weights were measured at the end of the experiment. Plasma Re and Se concentrations were assayed by an inductively coupled plasma sector field mass spectrometry instrument (ICP-sf-MS).
Results:
The weight of the tumors did not vary in treated versus non-treated mice. The limit of detection (LOD) of Re was 0.34 nmol/l. Plasma Re concentrations were 14±20 nmol/l at doses of 0.1 mg/kg, and increased at higher doses, up to 792±167 nmol/l at doses of 10 mg/kg. Plasma Se concentrations were significantly increased in mice treated with the dose of 0.1 mg/kg (4,262±1,511 nmol/l) versus controls (1,262±888 nmol/l), but not from 0.1 to 1 mg/kg, nor from 1 to 10 mg/kg.
Conclusion:
The 0.1 mg/kg dose of Re-diSe resulted in detectable plasma Re concentrations and significantly increased plasma Se concentrations. In the future, doses as low as 0.1 mg/kg of Re-diSe will be tested, exploring its potential immune interest as a metronomic schedule of treatment, but in mouse models that readily develop extensive metastatic disease.
... In this context, it is important to highlight that macrophages are professional phagocytic cells which play a central role in host defense and are responsible for in vivo nanoparticle trafficking [128]. Macrophages have functional plasticity that allows them to switch between M1 pro-inflammatory and M2 anti-inflammatory phenotypes, characterized by the secretion of different cytokines and the expression of specific cell surface markers [129]. These phenotypes are crucial in inflammation/healing processes, and, for this reason, the evaluation of the in vitro polarization of macrophages after exposure to nanomaterials is important to know the potential in vivo host response [130]. ...
Research in nanomaterials with applications in bone regeneration therapies has experienced a very significant advance with the development of bioactive mesoporous nanoparticles (MBNPs). These nanomaterials consist of small spherical particles that exhibit chemical properties and porous structures that stimulate bone tissue regeneration, since they have a composition similar to that of conventional sol–gel bioactive glasses and high specific surface area and porosity values. The rational design of mesoporosity and their ability to incorporate drugs make MBNPs an excellent tool for the treatment of bone defects, as well as the pathologies that cause them, such as osteoporosis, bone cancer, and infection, among others. Moreover, the small size of MBNPs allows them to penetrate inside the cells, provoking specific cellular responses that conventional bone grafts cannot perform. In this review, different aspects of MBNPs are comprehensively collected and discussed, including synthesis strategies, behavior as drug delivery systems, incorporation of therapeutic ions, formation of composites, specific cellular response and, finally, in vivo studies that have been performed to date.
... Macrophage activation produces distinct functional phenotypes that maintain homeostasis primarily by modulating the release of pro-and anti-inflammatory cytokines [27]. The M1 macrophage phenotype is activated by granulocyte-macrophage colony-stimulating factor (GM-CSF), and toll-like receptor (TLR) or IL-1R ligands and secretes pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, IL-12, IL-23 [28,29], tumor necrosis factor α (TNF-α) [30], and reactive oxygen intermediates [31]. Furthermore, they express specific biomarkers, including CD86, CD83, CD80, CD68, CD40, and major histocompatibility complex class I (MHC-I) [32]. ...
Cardiovascular diseases (CVDs) are the leading cause of hospitalization and death worldwide , especially in developing countries. The increased prevalence rate and mortality due to CVDs, despite the development of several approaches for prevention and treatment, are alarming trends in global health. Chronic inflammation and macrophage infiltration are key regulators of the initiation and progression of CVDs. Recent data suggest that epigenetic modifications, such as DNA methylation, posttranslational histone modifications, and RNA modifications, regulate cell development, DNA damage repair, apoptosis, immunity, calcium signaling, and aging in cardiomyocytes; and are involved in macrophage polarization and contribute significantly to cardiac disease development. Cardiac macrophages not only trigger damaging inflammatory responses during atherosclerotic plaque formation, myocardial injury, and heart failure but are also involved in tissue repair, re-modeling, and regeneration. In this review, we summarize the key epigenetic modifications that influence macrophage polarization and contribute to the pathophysiology of CVDs, and highlight their potential for the development of advanced epigenetic therapies.
... M1 and M2 MQs can also be converted to each other in response to the local microenvironments and the unbalanced M1/M2 phenotype is accompanied by the progression of in ammatory disorders [7][8][9]. Previous studies have shown that gluten peptides can induce activation of MQs to M1 pro-in ammatory phenotype in celiac disease [10,11]. Accordingly, controlling MQs polarization can be an attractive strategy for nding a novel therapeutic target for CD treatment. ...
Background and objective: Photobiomodulation (PBM) and Akkermansia muciniphila (A. muciniphila)have been shown to be effective in improving inflammatory conditions with positive effects on increasing the population of anti-inflammatory M2 macrophages. In this study, gliadin stimulated THP-1 derived macrophages were treated with A. muciniphila and PBM to evaluate their effects on promoting the polarization of M2 MQs.
Methods and Results: The human monocyte cell line (THP-1) was differentiated to Macrophages (MQ). MQs were stimulated with 200 μg/ml gliadin for 24 h and then were treated with PBM 810 nm alone and along with Akkermansia muciniphila for following 24 h to evaluate their effects on macrophages polarization. THP-1 derived MQs were also treated with PBM and A. muciniphila to evaluate their effects on non-stimulated MQs. CD11b, CD80, and CD206 levels were evaluated by flow cytometry technique. Moreover, the expression of some M1and M2-related cytokines were determined. PBM of gliadin stimulated MQs decreased IL-6 and increased TGF-β, IL-10 and TNF-α expression compared with gliadin exposed MQs. PBM along with A. muciniphila treatment induced IL-6, TNF-α, and IL-10 expression in MQs in comparison to the untreated group and also elevated TGF-β, IL-10 and TNF-α levels in gliadin triggered MQs related to gliadin stimulated MQ cells.
Conclusion: The result of this study showed the potential of PBMT and A. muciniphila to be used for modulating inflammatory responses and macrophages polarization, which may open new perspectives to find possible therapeutic target for celiac diseases.
... Макрофаги являются основными клетками системы врожденного иммунитета. Макрофаги присутствуют во многих тканях человеческого организма и могут адаптировать свой фенотип к изменяющемуся микроокружению [1,2]. Подобно дихотомии Т-клеток, в процессе которой происходит их разделение на Th1 и Th2 в зависимости от производимых ими цитокинов (INF-γ и IL-4 соответственно), описана дихотомия макрофагов, в соответствии с которой выделяют классически активированные макрофаги М1, и альтернативно активированные макрофаги M2 [3,4]. ...
Рассматривая микроокружение опухоли, исследователи отмечают большое количество типов клеток, его составляющих. Изучаются различные типы клеток, начиная от стромальных фибробластов и клеток иммунной системы, заканчивая эндотелиальными клетками и адипоцитами. Однако, несмотря на большое количество исследований, использование не стандартизированных маркеров стромальных клеток и подходов в оценке прогноза заболевания до сих пор не привели к их использованию в рутинной клинической практике. Для многих солидных опухолей неотъемлемой составляющей опухолевой стромы является резидентный микробиом, способный в значительной степени повлиять на характер активации иммунокомпетентных клеток микроокружения и анализ состава которого, на сегодняшний день также предлагается использовать в качестве прогностического маркера. В настоящем обзоре литературы проанализирована информация по микробиому и клеточному составу и фенотипу иммунологической составляющей опухолевой стромы новообразований легкого, механизмам их взаимодействия и влиянию этого взаимодействия на прогрессию опухоли. А также изучена возможность их использования для оценки прогноза заболевания и в качестве мишеней для терапии.
Objectives
Periodontitis is induced by the imbalance between osteoblast and osteoclast activity, which leads to periodontal tissue destruction. Macrophages play a vital role in periodontitis. However, the hypoxic periodontal environment will also induce macrophage apoptosis within a short time. Apoptotic bodies (ABs) are the major products generated from apoptotic cells, but whether macrophage‐derived ABs play a regulatory role as their mother cells in periodontitis remains unknown. In the present study, we aimed to investigate the effects of ABs on osteoblasts.
Method
ABs derived from hypoxia‐induced macrophages were co‐cultured with osteoblasts and the impact of ABs on osteoblast differentiation in vitro was assessed. In vivo, periodontitis model was established and macrophages‐derived ABs were injected into the gingival sulcus. The effects of ABs on periodontal bone resorption were determined.
Results
The results showed that ABs significantly inhibit osteoblast differentiation and promoted alveolar bone resorption in periodontitis. MicroRNA (miRNAs) array analysis was performed and revealed that miR‐483‐5p is the key miRNA in ABs. Dual luciferase reporter assays were performed and confirmed that miR‐483‐5p targeted Col1A1 mRNA and attenuated its expression.
Conclusion
Macrophage‐derived ABs inhibit osteoblast differentiation via the transfer of miR‐483‐5p, which downregulates Col1A1 expression and finally suppresses osteogenic activity.
The inflammatory response at the spinal cord injury (SCI) epicenter and heightened macrophage presence in the dorsal root ganglia (DRG) has been well characterized after SCI and correlates with neuropathic pain. CCL2, a chemokine that acts as a macrophage chemoattractant and neuromodulator, is implicated in pain development, however, the role of the CCL2-CCR2 axis in the development of pain after SCI has not been explored. Here, we examined the role of CCL2-CCR2 signaling in macrophage recruitment to the DRG as well as the prolonged presence of macrophages in the DRG on the development and persistence of pain after SCI. Adult female Sprague-Dawley rats received a moderate, unilateral C5 contusion. Sandwich ELISA revealed that CCL2 is upregulated in the ipsilesional C7 and C8 DRGs in the first 24 hours post injury (hpi) and returns to naive levels by 72 hpi. To prevent monocyte-derived macrophage recruitment to the DRG, additional SCI rats received vehicle or INCB3344, a CCR2 antagonist, intravenously at the time of SCI and at 24 and 48 hpi. INCB3344 administration induced transient forepaw allodynia at 7dpi in nearly all rats (88%) compared to only 33% in vehicle controls that resolves partially by 28 dpi, as measured by von Frey and mechanical conflict avoidance paradigms. As expected, qPCR analyses of whole DRG revealed that INCB3344 reduced macrophage markers and inflammatory cytokines in the ipsilesional C7 and C8 DRGs at 7 dpi compared to vehicle treated rats. By 28 dpi, there were no significant differences between INCB3344 or vehicle-treated groups, indicating that SCI-induced macrophage presence in the DRG is delayed by INCB3344 treatment. Moreover, gene expression of markers of macrophage polarity and cytokines suggest a pro-inflammatory environment in the DRG at 28dpi. DRG macrophage ablation via liposomal clodronate at 21dpi did not ameliorate hypersensitive pain behavior, though their ablation did reduce paw withdrawal thresholds in SCI rats that did not previously demonstrate pain behavior. Collectively, these data suggest that driving macrophages to a pro-reparative phenotype may be a viable and effective analgesic strategy that acts by modulating both the immune response and the experience of pain.
Purpose:
The conserved miR-183/96/182 cluster (miR-183C) regulates both corneal sensory innervation and corneal resident immune cells (CRICs). This study is to uncover its role in CRICs and in shaping the corneal cellular landscape at a single-cell (sc) level.
Methods:
Corneas of naïve, young adult [2 and 6 months old (mo)], female miR-183C knockout (KO) mice and wild-type (WT) littermates were harvested and dissociated into single cells. Dead cells were removed using a Dead Cell Removal kit. CD45+ CRICs were enriched by Magnetic Activated Cell Sorting (MACS). scRNA libraries were constructed and sequenced followed by comprehensive bioinformatic analyses.
Results:
The composition of major cell types of the cornea stays relatively stable in WT mice from 2 to 6 mo, however the compositions of subtypes of corneal cells shift with age. Inactivation of miR-183C disrupts the stability of the major cell-type composition and age-related transcriptomic shifts of subtypes of corneal cells. The diversity of CRICs is enhanced with age. Naïve mouse cornea contains previously-unrecognized resident fibrocytes and neutrophils. Resident macrophages (ResMϕ) adopt cornea-specific function by expressing abundant extracellular matrix (ECM) and ECM organization-related genes. Naïve cornea is endowed with partially-differentiated proliferative ResMϕ and contains microglia-like Mϕ. Resident lymphocytes, including innate lymphoid cells (ILCs), NKT and γδT cells, are the major source of innate IL-17a. miR-183C limits the diversity and polarity of ResMϕ.
Conclusion:
miR-183C serves as a checkpoint for CRICs and imposes a global regulation of the cellular landscape of the cornea.
Background:
Single-cell transcriptomic studies have greatly improved organ-specific insights into macrophage polarization states are essential for the initiation and resolution of inflammation in all tissues; however, such insights are yet to translate into therapies that can predictably alter macrophage fate.
Method:
Using machine learning algorithms on human macrophages, here we reveal the continuum of polarization states that is shared across diverse contexts. A path, comprised of 338 genes accurately identified both physiologic and pathologic spectra of "reactivity" and "tolerance", and remained relevant across tissues, organs, species, and immune cells (>12,500 diverse datasets).
Findings:
This 338-gene signature identified macrophage polarization states at single-cell resolution, in physiology and across diverse human diseases, and in murine pre-clinical disease models. The signature consistently outperformed conventional signatures in the degree of transcriptome-proteome overlap, and in detecting disease states; it also prognosticated outcomes across diverse acute and chronic diseases, e.g., sepsis, liver fibrosis, aging, and cancers. Crowd-sourced genetic and pharmacologic studies confirmed that model-rationalized interventions trigger predictable macrophage fates.
Interpretation:
These findings provide a formal and universally relevant definition of macrophage states and a predictive framework (http://hegemon.ucsd.edu/SMaRT) for the scientific community to develop macrophage-targeted precision diagnostics and therapeutics.
Funding:
This work was supported by the National Institutes for Health (NIH) grant R01-AI155696 (to P.G, D.S and S.D). Other sources of support include: R01-GM138385 (to D.S), R01-AI141630 (to P.G), R01-DK107585 (to S.D), and UG3TR003355 (to D.S, S.D, and P.G). D.S was also supported by two Padres Pedal the Cause awards (Padres Pedal the Cause/RADY #PTC2017 and San Diego NCI Cancer Centers Council (C3) #PTC2017). S.S, G.D.K, and D.D were supported through The American Association of Immunologists (AAI) Intersect Fellowship Program for Computational Scientists and Immunologists. We also acknowledge support from the Padres Pedal the Cause #PTC2021 and the Torey Coast Foundation, La Jolla (P.G and D.S). D.S, P.G, and S.D were also supported by the Leona M. and Harry B. Helmsley Charitable Trust.
A silk elastin-like protein (SELP) is an artificial compound with silk fibroin-like and elastin-like tandem repeats. The objective of this study is to evaluate the influence of SELP on the polarization of human monocytoma cell line (THP-1)-derived macrophages. When the macrophages of inflammation-type (M1) were cultured with different concentrations of SELP solution, the secretion of a pro-inflammatory cytokine, tumor necrotizing factor (TNF) -α was significantly suppressed at the higher concentrations. In addition, the secretion of an anti-inflammation cytokine, interleukin (IL)-10, was significantly enhanced from the macrophage of M0-, M1-, and M2-types. By the incubation with soluble SELP, the morphology of M2-type macrophages changed to be of an extended shape. Following incubation with the sponge of SELP, M0-type macrophages secreted IL-10 with time. It is concluded that the SELP itself in solution has an ability to induce the anti-inflammation of M2-type macrophages.
Macrophages are ancient, phagocytic immune cells thought to have their origins 500 million years ago in metazoan phylogeny. The understanding of macrophages has evolved to encompass their foundational roles in development, homeostasis, tissue repair, inflammation, and immunity. Notably, macrophages display high plasticity in response to environmental cues, capable of a strikingly wide variety of dynamic gene signatures and phenotypes. Macrophages are also involved in many pathological states including neural disease, asthma, liver disease, heart disease, cancer, and others. In cancer, most tumor-associated immune cells are macrophages, coined tumor-associated macrophages (TAMs). While some TAMs can display anti-tumor properties such as phagocytizing tumor cells and orchestrating an immune response, most macrophages in the tumor microenvironment are immunosuppressive and pro-tumorigenic. Macrophages have been implicated in all stages of cancer. Therefore, interest in manipulating macrophages as a therapeutic strategy against cancer developed as early as the 1970s. Companion dogs are a strong comparative immuno-oncology model for people due to documented similarities in the immune system and spontaneous cancers between the species. Data from clinical trials in humans and dogs can be leveraged to further scientific advancements that benefit both species. This review aims to provide a summary of the current state of knowledge on macrophages in general, and an in-depth review of macrophages as a therapeutic strategy against cancer in humans and companion dogs.
Macrophage is the immune phagocytic cell, playing variety of immunological and inflammatory reactions. The macrophage activation has been extensively studied in vitro using culture media like Dulbecco's modified Eagle’s medium (DMEM) and Ham's F-12 medium (F-12) in response to bacterial infection, tumor development, cytokines and so on. In the study of macrophage activation during co-culture with EL-4 tumor cells, we found different phenotypes of J774.1 macrophage-like cell line in F-12 and DMEM, when treated with lipopolysaccharide (LPS) and interferon-g (IFN- g). Among these phenotypes, nitric oxide (NO) production with corresponding inducible NO synthase (iNOS) expression was remarkable, showing higher in F-12 than in DMEM. Besides, O2-generating activity and production of interleukin-1b (IL-1b) were also higher in F-12 than DMEM, although production of tumor necrosis factor-a (TNF- a) was higher in DMEM than F-12. RT-PCR analysis revealed significantly higher expression of mRNA of iNOS, IL-1 b, IL-18, IkBa in F-12, but higher that of p65 and p105 in DMEM after treatment with LPS + IFN-g, suggesting these differences being induced at the transcriptional levels. Through investigation of critical factor(s) in these culture media that influence the activation phenotypes of the macrophages, we found that sodium bicarbonate (NaHCO3) concentrations in these culture media, 14 mM in Ham's F-12 and 44 mM in DMEM, were the key. Culture medium-induced differences in macrophage activation were also observed in RAW264.7 macrophage-like cell line and in mouse peritoneal macrophages. The recent studies suggested involvement of carrier (SLC) transporter gene expression and subsequent elevation of JAK/STAT signaling cascades in these NaHCO3 responses. Taken together, these results provide evidence for the importance of NaHCO3 in the culture medium in the macrophage activation in vitro, implying important insights to the NaHCO3 concentration in vivo in the body of patients suffering from inflammation, tumor development or immune disorders where macrophage activation is involved.
Yuting Yang,1,* Jin Zhao,2,* Chunmeng Jiang,1 Yue Zhang,1 Mei Han,1 Hui Liu1 1Department of Gastroenterology, Second Hospital of Dalian Medical University, Dalian, Liaoning, 116000, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, Air Force Medical Center, PLA, Beijing, 100000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hui Liu; Mei Han, Department of Gastroenterology, Second Hospital of Dalian Medical University, 467 Zhongshan Road, Shahekou Region, Dalian, Liaoning, 116000, People’s Republic of China, Email liuhuidoctor@dmu.edu.cn; hanmei@dmu.edu.cnAbstract: WKYMVm (Trp-Lys-Tyr-Met-Val-D-Met) is a synthetic hexapeptide identified as a potent agonist of FPRs. FPRs are widely expressed on the cell membrane of immune cells. Therefore, WKYMVm participates in the regulation of immune cells by activating FPRs, and plays a therapeutic role in infections, tumors, autoimmune diseases and so on. WKYMVm can promote the chemotactic migration, increase the bactericidal activity of neutrophils and monocytes. WKYMVm also regulates the number and polarization of macrophages, affects the maturation of DCs and the differentiation of T cells, and promotes the activation and chemotaxis of NK cells. These functions make WKYMVm a candidate drug for immunotherapy. In this paper, we summarize the regulatory effects and underlying mechanisms of WKYMVm on six immune cells (neutrophils, monocytes, macrophages, DCs, T cells and NK cells) to increase comprehensive understanding and promote further research on WKYMVm.Keywords: WKYMVm, FPRs, immune cells, chemotaxis, polarization
Orthopedic implants provide an avascular surface for microbial attachment and biofilm formation, impeding the entry of immune cells and the diffusion of antibiotics. The above is an important cause of dental and orthopedic implant-associated infection (IAI). For the prevention and treatment of IAI, the drawbacks of antibiotic resistance and surgical treatment are increasingly apparent. Due to their outstanding biological properties such as biocompatibility, immunomodulatory effects, and antibacterial properties, graphene-based nanomaterials (GBNs) have been applied to bone tissue engineering to deal with IAI, and in particular have great potential application in drug/gene carriers, multi-functional platforms, and coating forms. Here we review the latest research progress and achievements in GBNs for the prevention and treatment of IAI, mainly including their biomedical applications for antibacterial and immunomodulation effects, and for inducing osteogenesis. Furthermore, the biosafety of graphene family materials in bone tissue regeneration and the feasibility of clinical application are critically analyzed and discussed.
A silk elastin-like protein (SELP) is an artificial compound with silk fibroin-like and elastin-like tandem repeats. The objective of this study is to evaluate the influence of SELP on the polarization of mouse bone marrow-derived macrophages. When the macrophages of inflammation-type (M1) were cultured with different concentrations of SELP solution, the secretion of a pro-inflammatory cytokine, tumor necrotizing factor (TNF)-α, was significantly suppressed at the higher concentrations. In addition, the secretion of an anti-inflammation cytokine, interleukin (IL)-10, was significantly enhanced from the macrophage of an original type (M0). By the incubation with soluble SELP, the morphology of M0- and M1-type macrophages changed to be of a round shape with a large size. Following incubation with the sponge of SELP, the M0-type macrophages secreted IL-10 with time. When injected into an air pouch of mice subcutis which had been prepared by the injection of air, the SELP sponge and 5 wt % of SELP solution induced IL-10 secretion to a significantly high extent compared with the saline injection. Cells isolated from the air pouch 24 h after the injection were stained by the CD206 of a M2 marker. It is concluded that the SELP itself in solution has an ability to induce the anti-inflammation M2-type macrophages.
Traumatic Brain and Spinal Cord Injury comprehensively covers the medical and pathological issues related to neurotrauma and its often devastating consequences. Written by globally renowned experts in the field, both clinicians and researchers will find this book invaluable to update their knowledge. This volume is divided into two sections, one covering the brain, the other the spinal cord. Each section discusses the following topics: • The demographic in the developed and developing world where neurotrauma is witnessing a massive expansion • Major clinical issues including advanced semi-experimental monitoring techniques utilized by neurosurgeons and intensivists and the potential use of identifying markers of tissue injury • Overview of major pathophysiological changes • The development of animal models; successes and limitations • Past, current and future therapeutic strategies including rehabilitative opportunities. Presenting the most up-to-date clinical and experimental research in neurotrauma, this volume is essential reading for neurologists, neurosurgeons, intensive care physicians and rehabilitative physicians.
Traumatic Brain and Spinal Cord Injury comprehensively covers the medical and pathological issues related to neurotrauma and its often devastating consequences. Written by globally renowned experts in the field, both clinicians and researchers will find this book invaluable to update their knowledge. This volume is divided into two sections, one covering the brain, the other the spinal cord. Each section discusses the following topics: • The demographic in the developed and developing world where neurotrauma is witnessing a massive expansion • Major clinical issues including advanced semi-experimental monitoring techniques utilized by neurosurgeons and intensivists and the potential use of identifying markers of tissue injury • Overview of major pathophysiological changes • The development of animal models; successes and limitations • Past, current and future therapeutic strategies including rehabilitative opportunities. Presenting the most up-to-date clinical and experimental research in neurotrauma, this volume is essential reading for neurologists, neurosurgeons, intensive care physicians and rehabilitative physicians.
Traumatic Brain and Spinal Cord Injury comprehensively covers the medical and pathological issues related to neurotrauma and its often devastating consequences. Written by globally renowned experts in the field, both clinicians and researchers will find this book invaluable to update their knowledge. This volume is divided into two sections, one covering the brain, the other the spinal cord. Each section discusses the following topics: • The demographic in the developed and developing world where neurotrauma is witnessing a massive expansion • Major clinical issues including advanced semi-experimental monitoring techniques utilized by neurosurgeons and intensivists and the potential use of identifying markers of tissue injury • Overview of major pathophysiological changes • The development of animal models; successes and limitations • Past, current and future therapeutic strategies including rehabilitative opportunities. Presenting the most up-to-date clinical and experimental research in neurotrauma, this volume is essential reading for neurologists, neurosurgeons, intensive care physicians and rehabilitative physicians.
Traumatic Brain and Spinal Cord Injury comprehensively covers the medical and pathological issues related to neurotrauma and its often devastating consequences. Written by globally renowned experts in the field, both clinicians and researchers will find this book invaluable to update their knowledge. This volume is divided into two sections, one covering the brain, the other the spinal cord. Each section discusses the following topics: • The demographic in the developed and developing world where neurotrauma is witnessing a massive expansion • Major clinical issues including advanced semi-experimental monitoring techniques utilized by neurosurgeons and intensivists and the potential use of identifying markers of tissue injury • Overview of major pathophysiological changes • The development of animal models; successes and limitations • Past, current and future therapeutic strategies including rehabilitative opportunities. Presenting the most up-to-date clinical and experimental research in neurotrauma, this volume is essential reading for neurologists, neurosurgeons, intensive care physicians and rehabilitative physicians.
Traumatic Brain and Spinal Cord Injury comprehensively covers the medical and pathological issues related to neurotrauma and its often devastating consequences. Written by globally renowned experts in the field, both clinicians and researchers will find this book invaluable to update their knowledge. This volume is divided into two sections, one covering the brain, the other the spinal cord. Each section discusses the following topics: • The demographic in the developed and developing world where neurotrauma is witnessing a massive expansion • Major clinical issues including advanced semi-experimental monitoring techniques utilized by neurosurgeons and intensivists and the potential use of identifying markers of tissue injury • Overview of major pathophysiological changes • The development of animal models; successes and limitations • Past, current and future therapeutic strategies including rehabilitative opportunities. Presenting the most up-to-date clinical and experimental research in neurotrauma, this volume is essential reading for neurologists, neurosurgeons, intensive care physicians and rehabilitative physicians.
Traumatic Brain and Spinal Cord Injury comprehensively covers the medical and pathological issues related to neurotrauma and its often devastating consequences. Written by globally renowned experts in the field, both clinicians and researchers will find this book invaluable to update their knowledge. This volume is divided into two sections, one covering the brain, the other the spinal cord. Each section discusses the following topics: • The demographic in the developed and developing world where neurotrauma is witnessing a massive expansion • Major clinical issues including advanced semi-experimental monitoring techniques utilized by neurosurgeons and intensivists and the potential use of identifying markers of tissue injury • Overview of major pathophysiological changes • The development of animal models; successes and limitations • Past, current and future therapeutic strategies including rehabilitative opportunities. Presenting the most up-to-date clinical and experimental research in neurotrauma, this volume is essential reading for neurologists, neurosurgeons, intensive care physicians and rehabilitative physicians.
Traumatic Brain and Spinal Cord Injury comprehensively covers the medical and pathological issues related to neurotrauma and its often devastating consequences. Written by globally renowned experts in the field, both clinicians and researchers will find this book invaluable to update their knowledge. This volume is divided into two sections, one covering the brain, the other the spinal cord. Each section discusses the following topics: • The demographic in the developed and developing world where neurotrauma is witnessing a massive expansion • Major clinical issues including advanced semi-experimental monitoring techniques utilized by neurosurgeons and intensivists and the potential use of identifying markers of tissue injury • Overview of major pathophysiological changes • The development of animal models; successes and limitations • Past, current and future therapeutic strategies including rehabilitative opportunities. Presenting the most up-to-date clinical and experimental research in neurotrauma, this volume is essential reading for neurologists, neurosurgeons, intensive care physicians and rehabilitative physicians.
Traumatic Brain and Spinal Cord Injury comprehensively covers the medical and pathological issues related to neurotrauma and its often devastating consequences. Written by globally renowned experts in the field, both clinicians and researchers will find this book invaluable to update their knowledge. This volume is divided into two sections, one covering the brain, the other the spinal cord. Each section discusses the following topics: • The demographic in the developed and developing world where neurotrauma is witnessing a massive expansion • Major clinical issues including advanced semi-experimental monitoring techniques utilized by neurosurgeons and intensivists and the potential use of identifying markers of tissue injury • Overview of major pathophysiological changes • The development of animal models; successes and limitations • Past, current and future therapeutic strategies including rehabilitative opportunities. Presenting the most up-to-date clinical and experimental research in neurotrauma, this volume is essential reading for neurologists, neurosurgeons, intensive care physicians and rehabilitative physicians.
Traumatic Brain and Spinal Cord Injury comprehensively covers the medical and pathological issues related to neurotrauma and its often devastating consequences. Written by globally renowned experts in the field, both clinicians and researchers will find this book invaluable to update their knowledge. This volume is divided into two sections, one covering the brain, the other the spinal cord. Each section discusses the following topics: • The demographic in the developed and developing world where neurotrauma is witnessing a massive expansion • Major clinical issues including advanced semi-experimental monitoring techniques utilized by neurosurgeons and intensivists and the potential use of identifying markers of tissue injury • Overview of major pathophysiological changes • The development of animal models; successes and limitations • Past, current and future therapeutic strategies including rehabilitative opportunities. Presenting the most up-to-date clinical and experimental research in neurotrauma, this volume is essential reading for neurologists, neurosurgeons, intensive care physicians and rehabilitative physicians.
Traumatic Brain and Spinal Cord Injury comprehensively covers the medical and pathological issues related to neurotrauma and its often devastating consequences. Written by globally renowned experts in the field, both clinicians and researchers will find this book invaluable to update their knowledge. This volume is divided into two sections, one covering the brain, the other the spinal cord. Each section discusses the following topics: • The demographic in the developed and developing world where neurotrauma is witnessing a massive expansion • Major clinical issues including advanced semi-experimental monitoring techniques utilized by neurosurgeons and intensivists and the potential use of identifying markers of tissue injury • Overview of major pathophysiological changes • The development of animal models; successes and limitations • Past, current and future therapeutic strategies including rehabilitative opportunities. Presenting the most up-to-date clinical and experimental research in neurotrauma, this volume is essential reading for neurologists, neurosurgeons, intensive care physicians and rehabilitative physicians.
Expression of the macrophage mannose receptor is inhibited by interferon gamma (IFN-gamma), a T helper type 1 (Th-1)-derived lymphokine. Interleukin 4 (IL-4), a Th-2 lymphocyte product, upregulates major histocompatibility class II antigen expression but inhibits inflammatory cytokine production by macrophages. We have studied the effect of IL-4 on expression of the macrophage mannose receptor (MMR) by elicited peritoneal macrophages. We found that recombinant murine IL-4 enhances MMR surface expression (10-fold) and activity (15-fold), as measured by the respective binding and degradation of 125I-mannose-bovine serum albumin. Polymerase chain reaction analysis of cDNAs from purified primary macrophage populations revealed that MMR, but not lysozyme or tumor necrosis factor alpha, mRNA levels were markedly increased by IL-4. The above effects were associated with morphologic changes. These data establish IL-4 as a potent and selective enhancer of murine MMR activity in vitro. IL-4 induces inflammatory macrophages to adopt an alternative activation phenotype, distinct from that induced by IFN-gamma, characterized by a high capacity for endocytic clearance of mannosylated ligands, enhanced (albeit restricted) MHC class II antigen expression, and reduced proinflammatory cytokine secretion.
The production of cytokines in monocytes/macrophages is regulated by several different cytokines that have activating or inhibitory effects. Interleukin (IL)-10, IL-4, IL-13, and transforming growth factor (TGF)-beta are usually considered to be the most important macrophage-deactivating factors, with inhibitory effects on cytokine production. Unlike IL-10 and TGF-beta, which appear to act as downmodulators of many phagocytic cell functions, the mode of action of IL-4 and IL-13 is more complex. Addition of IL-4 and IL-13 to peripheral blood mononuclear cell (PBMC) cultures inhibited production of IL-12, tumor necrosis factor (TNF)-alpha, IL-10, and IL-1 beta induced by lipopolysaccharide (LPS) or Staphylococcus aureus added simultaneously with the cytokines. However, pretreatment of PBMC with IL-4 or IL-13 for > or = 20 h enhanced the production of IL-12 and TNF-alpha in response to LPS or S. aureus several fold in these cells; this IL-4-induced priming for the two cytokines was inhibited by anti-IL-4 neutralizing antibodies. IL-4 priming also enhanced the accumulation of IL-12 and TNF-alpha mRNA induced by LPS and S. aureus. The enhanced accumulation of transcripts for the IL-12 p35 and p40 chains by IL-4 priming was reflected in enhanced secretion of both the IL-12 free p40 chain and the p70 heterodimer. These results suggest an unexpected complexity in the regulatory role of IL-4 and IL-13 in immune responses.
Evidence is provided that macrophages can make M-1 or M-2 responses. The concept of M-1/M-2 fomented from observations that macrophages from prototypical Th1 strains (C57BL/6, B10D2) are more easily activated to produce NO with either IFN-gamma or LPS than macrophages from Th2 strains (BALB/c, DBA/2). In marked contrast, LPS stimulates Th2, but not Th1, macrophages to increase arginine metabolism to ornithine. Thus, M-1/M-2 does not simply describe activated or unactivated macrophages, but cells expressing distinct metabolic programs. Because NO inhibits cell division, while ornithine can stimulate cell division (via polyamines), these results also indicate that M-1 and M-2 responses can influence inflammatory reactions in opposite ways. Macrophage TGF-beta1, which inhibits inducible NO synthase and stimulates arginase, appears to play an important role in regulating the balance between M-1 and M-2. M-1/M-2 phenotypes are independent of T or B lymphocytes because C57BL/6 and BALB/c NUDE or SCID macrophages also exhibit M-1/M-2. Indeed, M-1/M-2 proclivities are magnified in NUDE and SCID mice. Finally, C57BL/6 SCID macrophages cause CB6F1 lymphocytes to increase IFN-gamma production, while BALB/c SCID macrophages increase TGF-beta production. Together, the results indicate that M-1- or M-2-dominant macrophage responses can influence whether Th1/Th2 or other types of inflammatory responses occur.
TNF-related activation-induced cytokine (TRANCE; also called receptor activator of NF-kappaB ligand (RANKL), osteoclast differentiation factor (ODF), osteoprotegerin ligand (OPGL), and TNFSF11) induces the differentiation of progenitors of the mononuclear phagocyte lineage into osteoclasts in the presence of M-CSF. Surprisingly, in view of its potent ability to induce inflammation and activate macrophage cytocidal function, TNF-alpha has also been found to induce osteoclast-like cells in vitro under similar conditions. This raises questions concerning both the nature of osteoclasts and the mechanism of lineage choice in mononuclear phagocytes. We found that, as with TRANCE, the macrophage deactivator TGF-beta(1) strongly promoted TNF-alpha-induced osteoclast-like cell formation from immature bone marrow macrophages. This was abolished by IFN-gamma. However, TRANCE did not share the ability of TNF-alpha to activate NO production or heighten respiratory burst potential by macrophages, or induce inflammation on s.c. injection into mice. This suggests that TGF-beta(1) promotes osteoclast formation not only by inhibiting cytocidal behavior, but also by actively directing TNF-alpha activation of precursors toward osteoclasts. The osteoclast appears to be an equivalent, alternative destiny for precursors to that of cytocidal macrophage, and may represent an activated variant of scavenger macrophage.
Atherosclerotic arteries frequently become calcified, and these calcium deposits are associated with a high risk of adverse clinical events. Descriptive studies suggest calcification is an organized and regulated process with many similarities to osteogenesis, yet the mechanism and its relationship to atherosclerosis remain largely unknown. In bone development and homeostasis, mineral deposition by osteoblasts and mineral resorption by osteoclasts are delicately balanced such that there is no overall gain or loss in bone mass. We hypothesize that there exists in arteries a mechanism that similarly balances mineral deposition with resorption. We propose that the cellular mediators of arterial mineral resorption are osteoclast-like cells (OLCs) derived from hematopoietic precursors of the mononuclear phagocytic lineage. In arterial microenvironments, mononuclear precursors are induced to differentiate toward OLCs by macrophage-colony stimulating factor and receptor activator of NF-kappaB ligand, both of which are necessary and sufficient for osteoclastogenesis and mineral resorption in bone. OLCs may participate in normal mineral homeostasis within the arterial wall or, alternatively, may be recruited to specific sites within developing plaque. Net calcium deposition occurs as a result of focal perturbation of the balance between the activity of osteoblast-like cells and OLCs. Our proposed mechanism thus views arterial mineral deposition not so much as an active pathological process, but as a localized failure of protective mechanisms that actively oppose mineral deposition within the disordered metabolic milieu of developing atherosclerotic plaque.
IL-10 regulates inflammation by reducing cytokine and chemokine production from activated macrophages. We performed microarray experiments to identify possible effector molecules of IL-10 and to investigate the global effect of IL-10 on the transcriptional response induced in LPS-activated macrophages. To exclude background effects of endogenous IL-10, macrophages from IL-10-deficient mice were used. IL-10 up-regulated expression of a small number of genes (26 and 37 after 45 min and 3 h, respectively), including newly identified and previously documented targets such as suppressor of cytokine signaling-3 and IL-1 receptor antagonist. However, the activation program triggered by LPS was profoundly affected by IL-10. IL-10 repressed 62 and further increased 15 of 259 LPS-induced genes. For all genes examined, the effects of IL-10 were determined to be STAT3-dependent. These results suggest that IL-10 regulates STAT3-dependent pathways that selectively target a broad component of LPS-induced genes at the mRNA level.
Interleukin-10 (IL-10) is a potent anti-inflammatory cytokine with numerous immunomodulatory effects, including the inhibition of proinflammatory cytokine production. The mechanisms by which IL-10 exerts these effects still remain largely unknown. As there is evidence that suggests IL-10-mediated cytokine suppression requires the induction of an intermediate gene, we have used gene-chip technology to identify IL-10-inducible genes in human monocytes. We have been able to identify a total of 19 genes that are up-regulated in response to IL-10. Three of these genes had been identified previously: IL-1ra, suppressors of cytokine signaling-3, and CD163; however, the other 16 represent newly identified IL-10-responsive genes. Further analysis of the regulation of eight of these genes showed a remarkable specificity to regulation by lipopolysaccharides (LPS) and IL-10, but not by other anti-inflammatory mediators such as IL-4 and transforming growth factor-beta, suggesting that two diverse stimuli such as IL-10 and LPS may engage common signaling mechanisms.
Evidence from postmortem analysis implicates the involvement of microglia in the neurodegenerative process of several degenerative neurological diseases, including Alzheimer's disease and Parkinson's disease. It remains to be determined, however, whether microglial activation plays a role in the initiation stage of disease progression or occurs merely as a response to neuronal death. Activated microglia secrete a variety of proinflammatory and neurotoxic factors that are believed to induce and/or exacerbate neurodegeneration. In this article, we summarize recent advances on the study of the role of microglia based on findings from animal and cell culture models in the pathogenesis of neurodegenerative diseases, with particular emphasis on Parkinson's disease. In addition, we also discuss novel approaches to potential therapeutic strategies.
Susceptibility to infectious diseases is directed, in part, by the interaction between the invading pathogen and host macrophages. This study examines the influence of genetic background on host-pathogen interactions, by assessing the transcriptional responses of macrophages from five inbred mouse strains to lipopolysaccharide (LPS), a major determinant of responses to gram-negative microorganisms.
The mouse strains examined varied greatly in the number, amplitude and rate of induction of genes expressed in response to LPS. The response was attenuated in the C3H/HeJlpsd strain, which has a mutation in the LPS receptor Toll-like receptor 4 (TLR4). Variation between mouse strains allowed clustering into early (C57Bl/6J and DBA/2J) and delayed (BALB/c and C3H/ARC) transcriptional phenotypes. There was no clear correlation between gene induction patterns and variation at the Bcg locus (Slc11A1) or propensity to bias Th1 versus Th2 T cell activation responses.
Macrophages from each strain responded to LPS with unique gene expression profiles. The variation apparent between genetic backgrounds provides insights into the breadth of possible inflammatory responses, and paradoxically, this divergence was used to identify a common transcriptional program that responds to TLR4 signalling, irrespective of genetic background. Our data indicates that many additional genetic loci control the nature and the extent of transcriptional responses promoted by a single pathogen-associated molecular pattern (PAMP), such as LPS.
The phenotypic differentiation of systemic macrophages that have infiltrated the central nervous system, pericytes, perivascular macrophages, and the "real" resident microglial cells is a major immunocytochemical and immunohistochemical concern for all users of cultures of brain cells and brain sections. It is not only important in assessing the purity of cell cultures; it is also of fundamental importance in the assessment of the pathogenetic significance of perivascular inflammatory phenomena within the brain. The lack of a single membranous and/or biochemical marker allowing conclusive identification of these cells is still a major problem in neurobiology. This review briefly discusses the functions of these cells and catalogs a large number of membranous and biochemical markers, which can assist in the identification of these cells.
To determine the kinetics of tissue macrophage and microglial engraftment after bone marrow (BM) transplantation, we have developed a model using the ROSA 26 mouse. Transplanted ROSA 26 cells can be precisely identified in recipient animals because they constitutively express β-galactosidase (β-gal) and neomycin resistance. B6/129 F2 mice were irradiated and transplanted with BM from ROSA 26 donors and their tissues (spleen, marrow, brain, liver, and lung) examined at various time points to determine the kinetics of engraftment. Frozen sections from transplanted animals were stained histochemically for β-gal to identify donor cells. At 1, 2, 6, and 12 months posttransplantation, 98% to 100% of granulocyte-macrophage colonies were of donor (ROSA 26) origin determined by β-gal staining and by neomycin resistance. Splenic monocytes/macrophages were 89% donor origin by 1 month confirming quick and complete engraftment of hematopoietic tissues. At this time, only rare ROSA 26 tissue macrophages or microglia were observed. Alveolar macrophage engraftment was evident by 2 months and had increased to 61% of total tissue macrophages at 1 year posttransplantation. The kinetics of liver Kupffer cell engraftment were similar to those seen in the lung. However, donor microglial engraftment remained only 23% of total microglia at 6 months and increased to only 30% by 1 year. Also, donor microglia were predominantly seen at perivascular and leptomeningeal, and not parenchymal, sites. The data show that microglia derive from BM precursors but turn over at a significantly slower rate than other tissue macrophages. No clinical or histological graft-versus-host disease was observed in the recipients of ROSA 26 BM. These kinetics may impact strategies for the gene therapy of lysosomal storage diseases. Because individual donor cells can be identified in situ, the ROSA 26 model should have many applications in transplantation biology including studies of homing and differentiation.
Expression of the macrophage mannose receptor is inhibited by interferon gamma (IFN-gamma), a T helper type 1 (Th-1)-derived lymphokine. Interleukin 4 (IL-4), a Th-2 lymphocyte product, upregulates major histocompatibility class II antigen expression but inhibits inflammatory cytokine production by macrophages. We have studied the effect of IL-4 on expression of the macrophage mannose receptor (MMR) by elicited peritoneal macrophages. We found that recombinant murine IL-4 enhances MMR surface expression (10-fold) and activity (15-fold), as measured by the respective binding and degradation of 125I-mannose-bovine serum albumin. Polymerase chain reaction analysis of cDNAs from purified primary macrophage populations revealed that MMR, but not lysozyme or tumor necrosis factor alpha, mRNA levels were markedly increased by IL-4. The above effects were associated with morphologic changes. These data establish IL-4 as a potent and selective enhancer of murine MMR activity in vitro. IL-4 induces inflammatory macrophages to adopt an alternative activation phenotype, distinct from that induced by IFN-gamma, characterized by a high capacity for endocytic clearance of mannosylated ligands, enhanced (albeit restricted) MHC class II antigen expression, and reduced proinflammatory cytokine secretion.
The production of cytokines in monocytes/macrophages is regulated by several different cytokines that have activating or inhibitory effects. Interleukin (IL)-10, IL-4, IL-13, and transforming growth factor (TGF)-beta are usually considered to be the most important macrophage-deactivating factors, with inhibitory effects on cytokine production. Unlike IL-10 and TGF-beta, which appear to act as downmodulators of many phagocytic cell functions, the mode of action of IL-4 and IL-13 is more complex. Addition of IL-4 and IL-13 to peripheral blood mononuclear cell (PBMC) cultures inhibited production of IL-12, tumor necrosis factor (TNF)-alpha, IL-10, and IL-1 beta induced by lipopolysaccharide (LPS) or Staphylococcus aureus added simultaneously with the cytokines. However, pretreatment of PBMC with IL-4 or IL-13 for > or = 20 h enhanced the production of IL-12 and TNF-alpha in response to LPS or S. aureus several fold in these cells; this IL-4-induced priming for the two cytokines was inhibited by anti-IL-4 neutralizing antibodies. IL-4 priming also enhanced the accumulation of IL-12 and TNF-alpha mRNA induced by LPS and S. aureus. The enhanced accumulation of transcripts for the IL-12 p35 and p40 chains by IL-4 priming was reflected in enhanced secretion of both the IL-12 free p40 chain and the p70 heterodimer. These results suggest an unexpected complexity in the regulatory role of IL-4 and IL-13 in immune responses.
The membrane molecules play an important role in all aspects of macrophage immunobiology. Some of the roles played by them are as receptors for growth and differentiation factors, as chemokines and lymphokines, as recognition and adhesion molecules for cellular and microbial ligands, and as regulators of cell signaling and gene expression. They determine and modulate homeostatic interactions with the host, contribute to innate and adaptive immunity, and mediate many of the pathological consequences of deficient or excessive activation. Some general aspects of macrophage heterogeneity are summarized and the differential expression of macrophage antigens is considered in this chapter as a function of tissue localization and cellular activity. Some of the differentiation antigens expressed by murine monocytes and macrophages are discussed—namely, EGF-TM7 antigens, IgSF antigens, and lectins. There are a number of molecules that function as scavenger receptors, several of which lack collagenous domains. Two such well-characterized antigens that play crucial roles in macrophage biology are scavenger receptor and MARCO.
Macrophages have specialized functions in different tissue microenvironments such as lymphohaemopoietic organs and the nervous system. Recently, progress has been made in defining cellular and molecular properties of isolated and tissue macrophages in the developing and adult animal.
Over the past decade, work from a number of laboratories has indicated that, under the proper conditions, the macrophage can express nonspecific effector cell function toward a variety of neoplastic cells (reviewed in Den Otter, 1981; Fidler and Raz, 1981; Keller, 1981; Lohmann-Matthes et al., 1981; Meltzer, 1981b; Piessens et al., 1981). While this type of macrophage tumoricidal activity does not require antibody or antibodylike specificity, it is nevertheless able to discriminate between normal cells and tumor cells (Hibbs, 1974; Piessens et al., 1975; Fidler et al.,1976). The currently accepted concept is that two signals are required to activate macrophages for tumor cell killing (Russell et al., 1977; Ruco and Meltzer, 1978a,b; Weinberg et al., 1978; Weinberg and Hibbs, 1979; Meltzer, 1981a,b; Pace and Russell, 1981). The first signal is a lymphokine that primes the macrophage and makes it receptive to a diverse group of substances that can act as second signals to trigger the development of full cytocidal activity. The lymphokine, denoted macrophage-activating factor (MAF), has been reported to alter a number of functional and biochemical properties in macrophage populations (reviewed in David and Remold, 1979; Rocklin et al., 1980). These alterations include increases in endocytic, biosynthetic, secretory, and effector cell functions as well as changes in membrane physiology and composition. However, since it is unclear whether all these alterations are effected by the same molecular species, it has become critical to define MAF in the context of the activity it induces. This chapter defines MAF exclusively as the factor that primes macrophages for nonspecific tumoricidal activity.
Macrophages play diverse roles in episodic T cell-mediated inflammatory diseases such as multiple sclerosis and rheumatoid arthritis, function as accessory cells for T cell activation, as pro-inflammatory cells, as effector cells which mediate tissue damage, and as anti-inflammatory cells which promote wound healing. In addition to the many roles of T cell-derived cytokines in differentially modulating these diverse macrophage activities, research over the last few years has demonstrated that contact-dependent signaling which occurs during T cell-macrophage adhesion is a critical triggering event in the activation of macrophage function. Substantial research emphasis has been placed on CD40 as a mediator of contact dependent signaling. However, other membrane-anchored receptor:ligand pairs may also contribute to the stimulation of macrophage function. This is a brief review of the rapidly expanding, but still incomplete, knowledge of how T cells, through both contact-dependent and cytokine signals, regulate macrophage function during inflammatory disease.
To determine the kinetics of tissue macrophage and microglial engraftment after bone marrow (BM) transplantation, we have developed a model using the ROSA 26 mouse. Transplanted ROSA 26 cells can be precisely identified in recipient animals because they constitutively express beta-galactosidase (beta-gal) and neomycin resistance. B6/129 F2 mice were irradiated and transplanted with BM from ROSA 26 donors and their tissues (spleen, marrow, brain, liver, and lung) examined at various time points to determine the kinetics of engraftment. Frozen sections from transplanted animals were stained histochemically for beta-gal to identify donor cells. At 1, 2, 6, and 12 months posttransplantation, 98% to 100% of granulocyte-macrophage colonies were of donor (ROSA 26) origin determined by beta-gal staining and by neomycin resistance. Splenic monocytes/macrophages were 89% donor origin by 1 month confirming quick and complete engraftment of hematopoietic tissues. At this time, only rare ROSA 26 tissue macrophages or microglia were observed. Alveolar macrophage engraftment was evident by 2 months and had increased to 61% of total tissue macrophages at 1 year posttransplantation. The kinetics of liver Kupffer cell engraftment were similar to those seen in the lung. However, donor microglial engraftment remained only 23% of total microglia at 6 months and increased to only 30% by 1 year. Also, donor microglia were predominantly seen at perivascular and leptomeningeal, and not parenchymal, sites. The data show that microglia derive from BM precursors but turn over at a significantly slower rate than other tissue macrophages. No clinical or histological graft-versus-host disease was observed in the recipients of ROSA 26 BM. These kinetics may impact strategies for the gene therapy of lysosomal storage diseases. Because individual donor cells can be identified in situ, the ROSA 26 model should have many applications in transplantation biology including studies of homing and differentiation.
Cultivation of human peripheral blood monocytes with granulocyte/macrophage colony stimulating factor (GM-CSF) and IL-4 facilitates generation of strongly antigen-presenting dendritic cells (DC). These monocyte-derived DC (mdDC) were used here to further delineate differentiation pathways in the myeloid lineage. Incubation of mdDC with TNF or soluble CD40L led to enhanced MHC and accessory surface antigen expression with significantly elevated T cell stimulatory activity, indicative of DC maturation. In contrast, after cytokine withdrawal or incubation with M-CSF, mdDC differentiated to macrophages. Cells became adherent, monocyte/macrophage surface markers were upregulated, and MHC and accessory surface proteins were downregulated. Furthermore, the multilaminar MHC class II compartments (MIIC) were lost and the T cell stimulating capacity largely diminished. Thus, mdDC show a high developmental plasticity by retaining their ability to become macrophages or to continue their differentiation towards mature DC.
Although initially considered merely "scavenger cells" that participate in immunologic responses only after B and T lymphocytes have performed their biological tasks, more recent evidence suggests that macrophages play a key role in host defense as well as in the maintenance of normal tissue structure and function. For macrophages to perform their biological functions, they must be activated. This involves up-regulation of an array of signaling pathways resulting in altered gene expression and increased biochemical and functional activity. Macrophages have been identified in almost all tissues of the body. However, the basal activity of these cells, as well as their ability to respond to inflammatory mediators, varies considerably with their location. In addition, even within a particular tissue, there is evidence of macrophage heterogeneity. The largest populations of macrophages in the body are located in the liver and lung. Because of the unique attributes of these tissues, hepatic and pulmonary macrophages play essential roles not only in nonspecific host defense but also in the homeostatic responses of these tissues. In this review, the functional and biochemical activities of macrophages localized in the liver and lungs are compared. Evidence suggests that these represent distinct cell populations with unique functions and responsiveness to inflammatory agents.
The role of macrophages in tumour growth and development is complex and multifaceted. Whilst there is limited evidence that tumour-associated macrophages (TAMs) can be directly tumouricidal and stimulate the anti-tumour activity of T cells, there is now contrasting evidence that tumour cells are able to block or evade the activity of TAMs at the tumour site. In some cases, tumour-derived molecules even redirect TAM activities to promote tumour survival and growth. Indeed, evidence has emerged for a symbiotic relationship between tumour cells and TAMs, in which tumour cells attract TAMs and sustain their survival, with TAMs then responding to micro-environmental factors in tumours such as hypoxia (low oxygen tension) by producing important mitogens as well as various growth factors and enzymes that stimulate tumour angiogenesis. This review presents evidence for the number and/or distribution of TAMs being linked to prognosis in different types of human malignancy. It also outlines the range of pro- and anti-tumour functions performed by TAMs, and the novel therapies recently devised using TAMs to stimulate host immune responses or deliver therapeutic gene constructs to solid tumours.
We examined the expression and function of beta-adrenergic receptor (beta-AR) subtypes in both isolated primary rat microglia and a rat microglial cell line. RT-PCR analyses revealed that microglia expressed beta(1)- and beta(2)-ARs but not beta(3)-ARs, whereas rat primary peritoneal macrophages expressed only beta(2)-ARs. Stimulation of beta-ARs on microglia by norepinephrine (NE) resulted in an increase in the level of intracellular cAMP and the subsequent expression of interleukin-1beta mRNA. These effects were prevented by propranolol. Similar results were obtained with other selective beta(1)-AR agonists and antagonists. beta(2)-ARs on microglia were also functional. It is possible that noradrenergic innervations participate in the control of microglial functions via beta(1)-ARs on microglia in the brain, because NE has high affinity for beta(1)- and beta(3)-ARs but little or no affinity for beta(2)-ARs. It seems physiologically significant that microglia can be controlled by NE, which predominates over epinephrine in the brain, whereas macrophages in peripheral tissues can be controlled by epinephrine, which is at higher levels in peripheral tissues.
Cytokines constitute a significant portion of the immuno- and neuromodulatory messengers that can be released by activated microglia. By virtue of potent effects on resident and invading cells, microglial cyto- and chemokines regulate innate defense mechanisms, help the initiation and influence the type of immune responses, participate in the recruitment of leukocytes to the CNS, and support attempts of tissue repair and recovery. Microglia can also receive cyto- and chemokine signals as part of auto- and paracrine communications with astrocytes, neurons, the endothelium, and leukocyte infiltrates. Strong responses and modulatory influences can be demonstrated, adding to the emerging view that microglial behavior is highly dependent on the (cytokine) environment and that reactions to a challenge may vary with the stimulation context. In principle, microglial activation aims at CNS protection. However, failed microglial engagement due to excessive or sustained activation could significantly contribute to acute and chronic neuropathologies. Dysregulation of microglial cytokine production could thereby promote harmful actions of the defense mechanisms, result in direct neurotoxicity, as well as disturb neural cell functions as they are sensitive to cytokine signaling.
The classical pathway of interferon-gamma-dependent activation of macrophages by T helper 1 (T(H)1)-type responses is a well-established feature of cellular immunity to infection with intracellular pathogens, such as Mycobacterium tuberculosis and HIV. The concept of an alternative pathway of macrophage activation by the T(H)2-type cytokines interleukin-4 (IL-4) and IL-13 has gained credence in the past decade, to account for a distinctive macrophage phenotype that is consistent with a different role in humoral immunity and repair. In this review, I assess the evidence in favour of alternative macrophage activation in the light of macrophage heterogeneity, and define its limits and relevance to a range of immune and inflammatory conditions.
Macrophage heterogeneity used to be a research topic on which the careers of many postdoctoral fellows were misspent. The lack of definitive markers and dubious biochemical assays prevented the unequivocal identification of specific cell subsets. There has now been significant progress in establishing the heterogeneity of activated macrophages. There are at least three distinct populations of macrophages, and each cell type appears to have different biological roles. The interplay among these populations of cells may help to shape not only the magnitude but also the character of the immune response. The manipulation of these cells may lead to new approaches to treat or prevent disease.
Osteoclasts are specialized cells derived from the monocyte/macrophage haematopoietic lineage that develop and adhere to bone matrix, then secrete acid and lytic enzymes that degrade it in a specialized, extracellular compartment. Discovery of the RANK signalling pathway in the osteoclast has provided insight into the mechanisms of osteoclastogenesis and activation of bone resorption, and how hormonal signals impact bone structure and mass. Further study of this pathway is providing the molecular basis for developing therapeutics to treat osteoporosis and other diseases of bone loss.
Unlike other brain structures, the hippocampus is able to produce new neurons throughout adult life. In their Perspective, [Kempermann and Neumann][1] discuss intriguing studies published here ([ Monje et al .][2]) and elsewhere showing that inflammation induced either by irradiation or lipopolysaccharide blocks hippocampal neurogenesis, which can be alleviated by treatment with nonsteroidal anti-inflammatory drugs.
[1]: http://www.sciencemag.org/cgi/content/full/302/5651/1689
[2]: http://www.sciencemag.org/cgi/content/short/302/5651/1760
Relapses of multiple sclerosis (MS) are considered to be the clinical expression of acute T-cell-mediated inflammatory demyelinating lesions disseminated in the CNS, whereas disease progression seems to result from widespread axonal degeneration. The pathophysiology of both disease components is incompletely understood. Astrocytes in MS lack beta(2)-adrenoceptors, which via cAMP-mediated processes inhibit the expression of major histocompatibility (MHC) class II molecules and stimulate glycogenolysis in normal conditions. In a pro-inflammatory CNS environment this beta(2)-adrenoceptor defect might allow astrocytes to transform into facultative antigen-presenting cells that can initiate the inflammatory cascade. The same receptor defect might impair astrocytic glycogenolysis, which normally generates lactate that is transported to axons as an energy source. Failure of axonal energy metabolism might result in axonal degeneration through mechanisms that involve intra-axonal accumulation of Ca(2+) ions and mitochondrial dysfunction. If this hypothesis is correct, therapies designed to elevate cAMP levels in astrocytes should reduce or prevent both relapses and progression of MS.
T cell signaling of macrophage activation
- R D Stout
- J Suttles
- R G Landes
Stout, R. D., Suttles, J. (1995) T cell signaling of macrophage activation. Cell Contact-Dependent and Cytokine Signals, Austin, TX, R. G. Landes, Springer-Verlag
Other functions, other genes: alternative activation of antigen-presenting cells
- Goerdt
Alternative activation of macrophages
- Gordon
The many faces of macrophage activation
- Mosser