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IL-1 and TNF expression propagates through mouse brain after a unilateral surgical lesion of the hippocampus. The lesion induced transient but long-lasting expression of both cytokines in neurons throughout the brain as evidenced by detection of IL-1 and TNF immunoreactivities in the striatum (a & b, respectively) 2 days, and cerebral cortex (d & e, respectively) and basal ganglia (g & h, respectively) 9 days, post lesion. Expression of TNF mRNA was detected by in situ hybridization in neurons (eg in cerebral cortex, i). The cytokines were not detected by immunocytochemistry in non-lesioned brain tissue (eg striatum (c) and cortex (f)). Magnification 250 ´.
Source publication
Interleukin-1 (IL-1) and tumor necrosis factor alpha (TNFalpha) are proinflammatory cytokines that are constitutively expressed in healthy, adult brain where they mediate normal neural functions such as sleep. They are neuromodulators expressed by and acting on neurons and glia. IL-1 and TNFalpha expression is upregulated in several important disea...
Contexts in source publication
Context 1
... 1 and TNF are induced in neurons after a surgical lesion to the right hemisphere and their expression propagates to various regions of the brain in a spatio- temporal pattern. 35 Twenty-four hours after the lesion, intense IL-1 and TNF ir appears in the striatum in the right hemisphere, ie, at a distance from the lesion (Figure 1a and b) but, not in the hippocampus itself. IL-1R density decreases, IL-1Ra mRNA level strongly increases and IL-1 ( and ) mRNA levels remain unchanged around the lesion. ...
Context 2
... to 5 days after the lesion, IL-1 and TNF ir increase and spread to the ipsilateral frontal cortex and thalamus and, after 6 days, to the contralateral frontal cortex, thalamus and striatum. At the peak of expression, 9-12 days after the lesion, the expression extends to the rest of the cortex (Figure 1d and e), basal ganglia (Figure 1g and h), cere- bellum, hippocampus, amygdala, diagonal band of Broca, substantia nigra, hypothalamus and raphe. 37 These data suggest that the IL-1 signal consists of changes in concentration of specific IL-1 family mem- bers. ...
Context 3
... to 5 days after the lesion, IL-1 and TNF ir increase and spread to the ipsilateral frontal cortex and thalamus and, after 6 days, to the contralateral frontal cortex, thalamus and striatum. At the peak of expression, 9-12 days after the lesion, the expression extends to the rest of the cortex (Figure 1d and e), basal ganglia (Figure 1g and h), cere- bellum, hippocampus, amygdala, diagonal band of Broca, substantia nigra, hypothalamus and raphe. 37 These data suggest that the IL-1 signal consists of changes in concentration of specific IL-1 family mem- bers. ...
Context 4
... propagation of cytokine signals, like epi- leptogenic seizure activity, depends on where in the brain they originate. IL-1 and TNF are synthesized by those neurons where the ir is detected, as judged by detection of their mRNA in situ (eg Figure 1i). 35 This suggests that the cytokines remain cell-bound rather than diffuse to activate distant cells. ...
Context 5
... suggests that neuronal pro- jections are a likely pathway for the propagation of cytokine signals. However, early expression of IL-1 and TNF in the striatum, including the dorsal part which is not directly connected to the hippocampus, and the later expression in the cerebellum, renders the interpretation of propagation via neuronal projections incomplete (Figures 1 and 4). Propagation via neuronal projections and/or diffusion through parenchyma or CSF is not completely compatible with the topographic distribution of cytokine-expressing neurons after the lesion to the hippocampus. ...
Citations
... 9,10 Similarly to infection, environmental and psychological stressors may be linked to immune activation and proinflammatory cytokine release 11,12 as well as to changes in mood and pathologic pain ( Fig. 1-3). 8,9,13 INFLAMMATION AND THE BRAIN The brain monitors the peripheral innate immune response using different immune-tobrain communication pathways [14][15][16][17][18] that act in parallel and, when activated, lead to the production of proinflammatory cytokines by central nervous system (CNS) parenchymal macrophages, called local microglial macrophages. The receptors for these mediators are expressed by both neuronal and non-neuronal brain cells, 12 but the brain circuitry that mediates the behavioral effects of cytokines remains mostly unclear. ...
... Dantzer et al., proposed a neural pathway where the locally produced cytokines can stimulate primary afferent nerves, such as the vagus nerve, and eventually alter brain chemistry and lead to depression via immune-to-brain communication [105]. Another proposed mechanism is the humoral pathway, where Toll-like receptors on macrophages produce inflammatory cytokines that cross the blood-brain barrier (BBB) by diffusion [106]. A third pathway includes transportation of cytokines across the BBB via cytokine transporters [107]. ...
Depression is a common and devastating mental illness associated with increased morbidity and mortality, partially due to elevated rates of suicidal attempts and death. Select patients with end-stage heart failure on a waiting-list for a donor heart undergo left ventricular assist device (LVAD) implantation. The LVAD provides a circulatory flow of oxygenated blood to the body, mimicking heart functionality by operating on a mechanical technique. LVAD improves functional capacity and survivability among patients with end-stage heart failure. However, accumulating data suggests that LVAD recipients suffer from an increased incidence of depression and suicide attempts. There is scarce knowledge regarding the pathological mechanism and appropriate treatment approach for depressed LVAD patients. This article summarizes the current evidence on the association between LVAD implantation and occurrence of depression, suggesting possible pathological mechanisms underlying the device-associated depression and reviewing the current treatment strategies. The summarized data underscores the need for a rigorous pre-(LVAD)-implantation psychiatric evaluation, continued post-implantation mental health assessment, and administration of antidepressant treatment as necessary.
... However, these long-term changes may lead to neurodegeneration and cachexia [14]. The action of cytokines occurs mainly in the hypothalamus, as it is a circumventricular organ and does not present a blood-brain barrier [15]. The hypothalamus is the regulating center of appetite, muscle mass and energy homeostasis [16]. ...
A high-protein hypercaloric diet enriched with glutamine and omega-3 polyunsaturated fatty acids was called an onco-diet. The goal was to verify the modulation of the inflammatory response and body composition of female dogs with mammary tumor after mastectomy, during onco-diet consumption, using a randomized, double-blinded, clinical trial. Six bitches (average age of 8.6 years) were allocated into Control Group-diet without glutamine, EPA and DHA supplementation; and six bitches (10.0 years) were allocated into Test-diet enriched with glutamine and omega-3. Serum measurements of TNF-α, IL-6, IL-10, IGF-1, C-reactive protein and determination of body composition were performed at pre- and post-surgical times. Statistical tests were used to compare the nutrient intake and dietary effects on inflammatory variables between the diets. No differences in concentrations of different cytokines (p>0.05) and C-reactive protein (CRP) (p = 0.51) were observed between the groups. The test group had a higher concentration of IGF-1 (p<0.05), higher percentage of muscle mass (p<0.01) and lower body fat (p<0.01), but the difference was present from initial and throughout the study. Onco-diet, enriched with glutamine and omega-3, in the amounts evaluated in this study, was not sufficient to modulate the inflammation and body composition of female dogs with mammary tumors submitted to unilateral mastectomy.
... It is possible that T cells penetrate the CNS parenchyma, but rarely and for very short periods of time [46]. They may also affect the CNS through the release of cytokines into the bloodstream, penetrating the blood-brain barrier (BBB) by volume diffusion, transport systems [47] or CD4 T cells trafficking across the choroid plexus and meninges [8]. Another pathway proposed for the entry of immune cells and their products into the brain is via the circumventricular organs (CVOs) [48,49]. ...
The immune and nervous systems can be thought of as cognitive and plastic systems, since they are both involved in cognition/recognition processes and can be architecturally and functionally modified by experience, and such changes can influence each other's functioning. The immune system can affect nervous system function depending on the nature of the immune stimuli and the pro/anti-inflammatory responses they generate. Here we consider interactions between the immune and nervous systems in homeostasis and disease, including the beneficial and deleterious effects of immune stimuli on brain function and the impact of severe and non-severe malaria parasite infections on neurocognitive and behavioral parameters in human and experimental murine malaria. We also discuss the effect of immunization on the reversal of cognitive deficits associated with experimental non-severe malaria in a model susceptible to the development of the cerebral form of the illness. Finally, we consider the possibility of using human vaccines, largely exploited as immune-prophylactics for infectious diseases, as therapeutic tools to prevent or mitigate the expression of cognitive deficits in infectious and chronic degenerative diseases.
... although the temporal changes in plasma levels of these circulating inflammatory markers was not determined in this work, and did not account for regional differences of cytokines profiles in the brain, a number or works have shown that synthesis and secretion of various pro-inflammatory cytokines in the periphery elicited centrally or systematically are determined by its specific spatio-temporal patterns. temporal profiles of peripheral cytokines after stimulation with lPs may differ on its route of administration, i.e. intraperitoneal vs. intravenous [41,42]. in a different animal setting, it was shown that repeated dose of lPs intraperitoneally caused neuroinflammation via activation of pro-inflammatory cytokines tNf-α and PGe 2 in lPs-induced rats and that treatment with ethanol ca extract at doses of 300 and 350 mg/kg were able to reduce the levels of both mediators [14]. Based on the findings in this study, we interpret our present data as suggesting that differential cytokines responses in the blood after single insult of lPs may play an important role in mediating long-lasting inflammatory responses which gradually leads to neurodegeneration. ...
Background and aim
Centella asiatica (L.) Urb. (Apiaceae) is a renowned medicinal plant being used in the Ayurvedic system for its pharmacological effects on the central nervous system such as rejuvenating, sedative, anxiolytic and memory-enhancing properties. The present study was designed to investigate the effect of Centella asiatica (CA) extract on inflammatory responses induced by lipopolysaccharide (LPS) and resulting changes in cognitive behavior.
Materials and methods
Adult male Sprague-Dawley rats were divided into 4 groups as control, LPS, CA and LPS + CA. The treatments with LPS (5 mg/kg) were intraperitoneally (i.p) injected on day 4 and CA ethanol extract (200 mg/kg) were given orally for 14 days. Morris Water Maze (MWM) test was performed to assess spatial learning and memory performance. Acute oral toxicity of the extract at the highest dose of 5000 mg/kg was also conducted.
Results
Single administration of LPS was able to significantly elicit learning and memory impairment (p < .05) when compared to the control groups. Treatment with CA significantly improved the impaired learning ability in which the LPS + CA rats took the shortest time and route to find the hidden platform (15.85 ± 2.68 s (p < .001); 352.43 ± 88.10 cm (p < .001) on day 5) and induced differential cytokine responses in the blood. No mortality and no significant variation in the body and organ weights between the control and the treated group was observed after 14 days of acute toxicity study. Hematological analysis and biochemical parameters revealed no toxic effects of the extract. Pathologically, neither gross abnormalities nor histopathological changes were observed.
Discussion and conclusion
Centella asiatica extract exhibited significant learning and memory enhancement potential in animal model. Hence, indicating its putative preventive therapeutic effects in neuroinflammation related diseases.
KEY MESSAGE
A single dose of lipopolysaccharide (LPS) (5 mg/kg) administered systemically to mimic the consequences of LPS-induced inflammatory responses was able to affect some behavioral modification of spatial memory at the time point of study.
The study showed that the learning capability during the training trial was restored or ameliorated with the pre-emptive treatment of Centella asiatica extract (200 mg/kg).
Centella asiatica extract improves spatial memory, learning deficits and regulates proinflammatory responses in systemic LPS-treated rats.
... Acute injuries also result in increased TNFa expression (Fan et al, 1996). Besides its role in inflammation, TNFa can be found in non-inflamed brains at both mRNA and protein levels (Vitkovic et al, 2000), suggesting additional functions in brain physiology. ...
In the last two decades, the term synaptopathy has been largely used to underline the concept that impairments of synaptic structure and function are the major determinant of brain disorders, including neurodevelopmental disorders. This notion emerged from the progress made in understanding the genetic architecture of neurodevelopmental disorders, which highlighted the convergence of genetic risk factors onto molecular pathways specifically localized at the synapse. However, the multifactorial origin of these disorders also indicated the key contribution of environmental factors. It is well recognized that inflammation is a risk factor for neurodevelopmental disorders, and several immune molecules critically contribute to synaptic dysfunction. In the present review, we highlight this concept, which we define by the term "immune-synaptopathy," and we discuss recent evidence suggesting a bi-directional link between the genetic architecture of individuals and maternal activation of the immune system in modulating brain developmental trajectories in health and disease.
... However, recent studies have identified distinct transport molecules present along the BBB that can actively transport the pro-inflammatory cytokines. In addition, systemic inflammation can alter BBB, making it more permeable to immune molecules [62]. ...
Depression is the leading cause of disability worldwide, contributing to the global disease burden. From above, it is a priority to investigate models that fully explain its physiopathology to develop new treatments. In the last decade, many studies have shown that gut microbiota (GM) dysbiosis influences brain functions and participate, in association with immunity, in the pathogenesis of depression. Thereby, GM modulation could be a novel therapeutic target for depression. This review aims to evidence how the GM and the immune system influence mental illness, particularly depression. Here, we focus on the communication mechanisms between the intestine and the brain and the impact on the development of neuroinflammation contributing to the development of Major Depressive Disorder (MDD). However, most of the current findings are in animal models, suggesting the need for studies in humans. In addition, more analysis of metabolites and cytokines are needed to identify new pathophysiological mechanisms improving anti-depression treatments.
... The accumulation of activated glial cell is usually associated with a flux of blood-borne immune cells and cytokines [51] aligning with our observations. These cytokines can subsequently alter neuron excitability [52] and attenuate the effects by enhancing cytokine production in neurons and their surrounding cells [53][54][55][56]. Enhanced neuroinflammation is also known to cause chronic neuropathic pain in literature [57,58]. ...
Spinal cord injury is a severely debilitating condition affecting a significant population in the USA. Spinal cord injury patients often have increased risk of developing persistent neuropathic pain and other neurodegenerative conditions beyond the primary lesion center later in their life. The molecular mechanism conferring to the "latent" damages at distal tissues, however, remains elusive. Here, we studied molecular changes conferring abnormal functionality at distal spinal cord (T12) beyond the lesion center (T10) by combining next-generation sequencing (RNA- and bisulfite sequencing), super-resolution microscopy, and immunofluorescence staining at 7 days post injury. We observed significant transcriptomic changes primarily enriched in neuroinflammation and synaptogenesis associated pathways. Transcription factors (TFs) that regulate neurogenesis and neuron plasticity, including Egr1, Klf4, and Myc, are significantly upregulated. Along with global changes in chromatin arrangements and DNA methylation, including 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC), bisulfite sequencing further reveals the involvement of DNA methylation changes in regulating cytokine, growth factor, and ion channel expression. Collectively, our results pave the way towards understanding transcriptomic and epigenomic mechanism in conferring long-term disease risks at distal tissues away from the primary lesion center and shed light on potential molecular targets that govern the regulatory mechanism at distal spinal cord tissues.
... [6][7][8] Similar to microglia, astrocytes become reactive, can proliferate, and synthesize ILs, TNFα, and ROS. 9,10 The physiological purpose of inflammation is to restore disturbed tissue homeostasis. However, unique immunosuppressive inflammation associated with glioblastoma multiforme (GBM) promotes tumor development, migration, invasion, proliferation, resistance to apoptosis, and maintenance of stem cell-like properties. ...
The precise physiological functions and mechanisms regulating RNase Regnase‐2 (Reg‐2/ZC3H12B/MCPIP2) activity remain enigmatic. We found that Reg‐2 actively modulates neuroinflammation in nontransformed cells, including primary astrocytes. Downregulation of Reg‐2 in these cells results in increased mRNA levels of proinflammatory cytokines IL‐1β and IL‐6. In primary astrocytes, Reg‐2 also regulates the mRNA level of Regnase‐1 (Reg‐1/ZC3H12A/MCPIP1). Reg‐2 is expressed at high levels in the healthy brain, but its expression is reduced during neuroinflammation as well as glioblastoma progression. This process is associated with the upregulation of Reg‐1. Conversely, overexpression of Reg‐2 is accompanied by the downregulation of Reg‐1 in glioma cells in a nucleolytic NYN/PIN domain‐dependent manner. Interestingly, low levels of Reg‐2 and high levels of Reg‐1 correlate with poor‐glioblastoma patients' prognoses. While Reg‐2 restricts the basal levels of proinflammatory cytokines in resting astrocytes, its expression is reduced in IL‐1β‐activated astrocytes. Following IL‐1β exposure, Reg‐2 is phosphorylated, ubiquitinated, and degraded by proteasomes. Simultaneously, the Reg‐2 transcript is destabilized by tristetraprolin (TTP) and Reg‐1 through the AREs elements and conservative stem‐loop structure present in its 3′UTR. Thus, the peer‐control loop, of Reg‐1 and Reg‐2 opposing each other, exists. The involvement of TTP in Reg‐2 mRNA turnover is confirmed by the observation that high TTP levels correlate with the downregulation of the Reg‐2 expression in high‐grade human gliomas. Additionally, obtained results reveal the importance of Reg‐2 in inhibiting human and mouse glioma cell proliferation. Our current studies identify Reg‐2 as a critical regulator of homeostasis in the brain.
... (3) Circulating cytokines reach outside-BBB organs. There, cells expressing toll-like receptors react to the increased inflammation by releasing pro-inflammatory cytokines, which may reach the brain by volume diffusion (Vitkovic et al., 2000b;McCusker and Kelley, 2013;Sankowski et al., 2015). When triggered peripherally, these three routes activate brain microglia and astrocytes to create proinflammatory cytokines, spreading the signal into the neuronal environment (Dantzer et al., 2008;Sankowski et al., 2015). ...
Background
The development of mild cognitive impairment (MCI) and Alzheimer’s disease (AD) may be associated with an inflammatory process. Inflammatory cytokines may be a surrogate for systemic inflammation leading to worsening neurological function. We aim to investigate the association between cognitive impairment and inflammation by pooling and analyzing the data from previously published studies.Methods
We performed a systematic literature search on MEDLINE, PubMed, Embase, Web of Science, and Scopus for prospective longitudinal and cross-sectional studies evaluating the relationship between inflammation and cognitive functions.ResultsA total of 79 articles were included in our systematic review and meta-analysis. Pooled estimates from cross-sectional studies have demonstrated an increased level of C-reactive protein (CRP) [Hedges’s g 0.35, 95% CI (0.16, 0.55), p < 0.05], IL-1β [0.94, 95% CI (−0.04, 1.92), p < 0.05], interleukin-6 (IL-6) [0.46, 95% CI (0.05, 0.88), p < 0.005], TNF alpha [0.22, 95% CI (−0.24, 0.68), p < 0.05], sTNFR-1 [0.74, 95% CI (0.46, 1.02), p < 0.05] in AD compared to controls. Similarly, higher levels of IL-1β [0.17, 95% CI (0.05, 0.28), p < 0.05], IL-6 [0.13, 95% CI (0.08, 0.18), p < 0.005], TNF alpha [0.28, 95% CI (0.07, 0.49), p < 0.05], sTNFR-1 [0.21, 95% CI (0.05, 0.48), p < 0.05] was also observed in MCI vs. control samples. The data from longitudinal studies suggested that levels of IL-6 significantly increased the risk of cognitive decline [OR = 1.34, 95% CI (1.13, 1.56)]. However, intermediate levels of IL-6 had no significant effect on the final clinical endpoint [OR = 1.06, 95% CI (0.8, 1.32)].Conclusion
The data from cross-sectional studies suggest a higher level of inflammatory cytokines in AD and MCI as compared to controls. Moreover, data from longitudinal studies suggest that the risk of cognitive deterioration may increase by high IL-6 levels. According to our analysis, CRP, antichymotrypsin (ACT), Albumin, and tumor necrosis factor (TNF) alpha may not be good surrogates for neurological degeneration over time.
