Correction: Prophylactic versus Therapeutic Fingolimod: Restoration of Presynaptic Defects in Mice Suffering from Experimental Autoimmune Encephalomyelitis
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PROVIDER: S-EPMC10547186 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND AND PURPOSE Alterations of glutamate-mediated synaptic transmission occur early during neuroinflammatory insults, and lead to degenerative neuronal damage in multiple sclerosis (MS) and also in experimental autoimmune encephalomyelitis (EAE), which is a murine model of MS. Fingolimod is an effective orally active agent for the treatment of MS, affecting lymphocyte invasion of the brain. However, it is still unclear if fingolimod can be neuroprotective in this disorder. EXPERIMENTAL APPROACH Using neurophysiological recordings and morphological evaluation of dendritic integrity, we evaluated the effects of oral fingolimod on the clinical score of EAE mice in order to determine whether the compound was associated with preservation of synaptic transmission. KEY RESULTS Oral fingolimod prevented and reversed the pre- and postsynaptic alterations of glutamate transmission in EAE mice. These effects were associated with a clear amelioration of the clinical deterioration seen in EAE mice, and with a significant inhibition of neuronal dendritic pathology. Fingolimod did not alter the spontaneous excitatory postsynaptic currents in control animals, suggesting that only the pathological processes behind the inflammation-induced defects in glutamate transmission were modulated by this compound. CONCLUSIONS AND IMPLICATIONS The beneficial effects of fingolimod on the clinical, synaptic and dendritic abnormalities of murine EAE might correlate with the neuroprotective actions of this agent, as observed in MS patients. LINKED ARTICLE This article is commented on by Gillingwater, pp. 858-860 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2011.01612.x.
| S-EPMC3312484 | biostudies-literature
Project description:BackgroundThe essential amino acid, tryptophan, is predominantly metabolised through the kynurenine pathway (KP) to generate kynurenine, an aryl-hydrocarbon receptor (AhR) pro-ligand that exerts its effects in a ligand-dependent manner. Interaction between kynurenine and the AhR is an effector mechanism of immunosuppression. We previously found that the KP is involved in multiple sclerosis (MS) disease progression. We postulated that AhR activation by kynurenine might be neuroprotective by encouraging differentiation of Tregs. In this study, we assess both the prophylactic and therapeutic efficiency of kynurenine on disease severity and progression in mice with experimental autoimmune encephalomyelitis (EAE), an MS model.MethodsMyelin oligodendrocyte glycoprotein induced EAE mice (n = 6 per group) were treated with 200 mg/kg L-kynurenine once daily for 10 days beginning on either day 1 of EAE induction (prophylactic) or once they demonstrated motor weakness (therapeutic). Clinical disease severity measured by disease score, time on rotarod, and body weight.ResultsThe prophylactic kynurenine treatment significantly (P < .0001) prevented the development of a more severe disease course with mice demonstrating diminished relapse rate and improved clinical and behavioural outcomes. However, therapeutic kynurenine did not significantly (P = .4463) decrease the clinical signs until 36 days following induction of disease; after 36 days, it also significantly (P = .0479) reduced disease relapse. Mean body weight measurements only correlated with time on rotarod (r = -.6410; P = .0007) but not clinical scores (r = .1925; P = .3674).ConclusionsKynurenine ameliorates EAE disease progression prophylactically and reduces relapses therapeutically. Further investigations are needed to elucidate the molecular mechanism explaining the therapeutic role of kynurenine for MS.
| S-EPMC9393931 | biostudies-literature
Project description:[This corrects the article DOI: 10.1371/journal.pone.0144847.].
| S-EPMC4856275 | biostudies-literature
Project description:Microbiome composition studies are increasingly shedding light on animal models of disease. This paper describes a protocol for analyzing the gut microbiome composition prior to and after the induction of mice to experimental autoimmune encephalomyelitis (EAE), the principal animal model of the human neuroinflammatory demyelinating disease multiple sclerosis (MS). We also address and provide data assessing the impact of mice reared in different animal facilities on EAE induction. Furthermore, we discuss potential regulators of the gut-microbiome-brain axis (GMBA) in relation to neuroinflammation and implications on demyelinating disease states. Our results suggest that mice reared in different animal facilities produce different levels of EAE induction. These results highlight the importance of accounting for consistent environmental conditions when inducing EAE and other animal models of disease. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Study of the composition of the gut microbiome in the neuroinflammatory model of experimental autoimmune encephalomyelitis Basic Protocol 2: Experimental procedures for DNA extraction and microbiome analysis.
| S-EPMC9540342 | biostudies-literature
Project description:Multiple sclerosis (MS) is the most common inflammatory disease of the central nervous system (CNS) most likely caused by autoreactive T cells. Mucosal-associated invariant T (MAIT) cells are characterized by a semi-invariant T cell receptor (TCR) with which they recognize 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU), a metabolite of the riboflavin (vitamin B2) pathway only present in yeast and bacteria. MAIT cells have been detected in inflamed brain lesions of MS patients. However, functional analyses of CNS-infiltrating MAIT cells are lacking and require a characterisation in the MS animal model experimental autoimmune encephalomyelitis (EAE).
2024-09-30 | GSE234291 | GEO
Project description:Multiple sclerosis (MS) is an autoimmune, neurodegenerative disease but the molecular mechanisms underlying neurodegenerative aspects of the disease are poorly understood. microRNAs (miRNAs) are powerful regulators of gene expression that regulate numerous mRNAs simultaneously and can thus regulate programs of gene expression. Here, we describe miRNA expression in neurons captured from mice subjected to experimental autoimmune encephalomyelitis (EAE), a model of central nervous system (CNS) inflammation. Lumbar motor neurons and retinal neurons were laser captured from EAE mice and miRNA expression was assessed by next-generation sequencing and validated by qPCR. We describe 14 miRNAs that are differentially regulated in both neuronal subtypes and determine putative mRNA targets though in silico analysis. Several upregulated neuronal miRNAs are predicted to target pathways that could mediate repair and regeneration during EAE. This work identifies miRNAs that are affected by inflammation and suggests novel candidates that may be targeted to improve neuroprotection in the context of pathological inflammation.
| S-EPMC6128870 | biostudies-literature
Project description:Focal cerebral ischemia and traumatic brain injury induce an escalating amount of cell death because of harmful mediators diffusing from the original lesion site. Evidence suggests that healthy cells surrounding these lesions attempt to protect themselves by producing endocannabinoids (eCBs) and activating cannabinoid receptors, the molecular target for marijuana-derived compounds. Indeed, activation of cannabinoid receptors reduces the production and diffusion of harmful mediators. Here, we provide evidence that an exception to this pattern is found in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. We show that cell damage induced by EAE does not lead to increase in eCBs, even though cannabinoid receptors are functional because synthetic cannabinoid agonists are known to confine EAE-induced lesions. This lack of eCB increase is likely due to IFN-gamma, which is released by primed T cells invading the CNS. We show that IFN-gamma disrupts the functionality of purinergic P2X7 receptors, a key step controlling eCB production by microglia, the main source of eCBs in brain. Accordingly, induction of EAE in P2X7-/- mice results in even lower eCB levels and more pronounced cell damage than in wild-type mice. Our data suggest that the high level of CNS IFN-gamma associated with EAE disrupts eCB-mediated neuroprotection while maintaining functional cannabinoid receptors, thus providing additional support for the use of cannabinoid-based medicine to treat multiple sclerosis.
| S-EPMC1458883 | biostudies-literature
Project description:The costimulatory CD40L-CD40 dyad plays a major role in multiple sclerosis (MS). CD40 is highly expressed on MHCII+ B cells, dendritic cells and macrophages in human MS lesions. Here we investigated the role of the CD40 downstream signaling intermediates TNF receptor-associated factor 2 (TRAF2) and TRAF6 in MHCII+ cells in experimental autoimmune encephalomyelitis (EAE). Both MHCII-CD40-Traf2-/- and MHCII-CD40-Traf6-/- mice showed a reduction in clinical signs of EAE and prevented demyelination. However, only MHCII-CD40-Traf6-/- mice displayed a decrease in myeloid and lymphoid cell infiltration into the CNS that was accompanied by reduced levels of TNF-α, IL-6 and IFN-γ. As CD40-TRAF6 interactions predominantly occur in macrophages, we subjected CD40flfl LysMcre mice to EAE. This myeloid-specific deletion of CD40 resulted in a significant reduction in EAE severity, reduced CNS inflammation and demyelination. In conclusion, the CD40-TRAF6 signaling pathway in MHCII+ cells plays a key role in neuroinflammation and demyelination during EAE. Concomitant with the fact that CD40-TRAF6 interactions are predominant in macrophages, depletion of myeloid CD40 also reduces neuroinflammation. CD40-TRAF6 interactions thus represent a promising therapeutic target for MS. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
| S-EPMC6519352 | biostudies-literature
Project description:One of the mitogen-activated protein kinases, p38, has been found to play a crucial role in various inflammatory responses. In this study, we analyzed the roles of p38? in multiple sclerosis, using an animal model, experimental autoimmune encephalomyelitis (EAE). p38?(+/-) mice (p38?(-/-) showed embryonic lethality) showed less severe neurological signs than WT mice. Adoptive transfer of lymph node cells (LNC) from sensitized WT mice with MOG(35-55) to naive WT-induced EAE was much more severe compared with the case using LNC from sensitized p38?(+/-) mice. Comprehensive analysis of cytokines from MOG(35-55)-challenged LNC by Western blot array revealed that production of IL-17 was significantly reduced by a single copy disruption of the p38? gene or a p38 inhibitor. Likewise, by a luciferase reporter assay, an electrophoresis mobility shift assay, and characterization of the relationship between p38 activity and IL-17 mRNA expression, we confirmed that p38 positively regulates transcription of the Il17 gene. Furthermore, oral administration of a highly specific p38? inhibitor (UR-5269) to WT mice at the onset of EAE markedly suppressed the progression of EAE compared with a vehicle group. These results suggest that p38? participates in the pathogenesis of EAE through IL-17 induction.
| S-EPMC3397849 | biostudies-literature
Project description:Multiple sclerosis, and its murine model experimental autoimmune encephalomyelitis (EAE), is a neurodegenerative autoimmune disease of the CNS characterized by T cell influx and demyelination. Similar to other autoimmune diseases, therapies can alleviate symptoms but often come with side effects, necessitating the exploration of new treatments. We recently demonstrated that the Cullin-RING E3 ubiquitin ligase 4b (CRL4b) aided in maintaining genome stability in proliferating T cells. In this study, we examined whether CRL4b was required for T cells to expand and drive EAE. Mice lacking Cul4b (Cullin 4b) in T cells had reduced EAE symptoms and decreased inflammation during the peak of the disease. Significantly fewer CD4+ and CD8+ T cells were found in the CNS, particularly among the CD4+ T cell population producing IL-17A, IFN-γ, GM-CSF, and TNF-α. Additionally, Cul4b-deficient CD4+ T cells cultured in vitro with their wild-type counterparts were less likely to expand and differentiate into IL-17A- or IFN-γ-producing effector cells. When wild-type CD4+ T cells were activated in vitro in the presence of the recently developed CRL4 inhibitor KH-4-43, they exhibited increased apoptosis and DNA damage. Treatment of mice with KH-4-43 following EAE induction resulted in stabilized clinical scores and significantly reduced numbers of T cells and innate immune cells in the CNS compared with control mice. Furthermore, KH-4-43 treatment resulted in elevated expression of p21 and cyclin E2 in T cells. These studies support that therapeutic inhibition of CRL4 and/or CRL4-related pathways could be used to treat autoimmune disease.
| S-EPMC11060073 | biostudies-literature