Experimental Autoimmune Encephalomyelitis Research Articles

Modulation of acetylcholine level by donepezil hydrochloride attenuates the severity of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis.

Dimethyl fumarate (DMF) is an oral therapy approved for the treatment of relapsing-remitting multiple sclerosis, and it is known to reduce disease severity in experimental autoimmune encephalomyelitis (EAE). Because self-reactive Th17 lymphocytes are thought to become activated in the gut before migrating to the central nervous system (CNS), we investigated how DMF modulates intestinal immune responses during EAE. Female C57BL/6J mice were immunized with MOG35-55 to induce EAE and treated with DMF (7.5 mg/kg, oral gavage, every 12 h) or vehicle starting at day 3 post-immunization (dpi). At the early chronic phase (d.p.i. 21), continuous DMF treatment reduced disease severity and CNS leukocyte infiltration. Notably, even short-term DMF administration (5 d) attenuated EAE compared to controls. To examine gut-specific effects, we profiled colonic gene expression after 5 d of treatment (dpi 8) using a NanoString autoimmune panel. We found that DMF downregulated genes associated with NF-κB and ERK1/2 signaling, pro-inflammatory cytokine production, and leukocyte migration in intestinal immune (myeloid) and epithelial cells. Flow cytometry analysis further demonstrated reduced interleukin (IL)-23a production by colonic macrophages and dendritic cells, thereby impairing pathogenic Th17 differentiation. Moreover, DMF decreased CXCR3, CCR6, and CXCR6 expression on MOG-reactive (V-β11+) Th17 cells, limiting their migratory potential to the CNS. Together, these findings show that DMF regulates Th17 differentiation and migration within the intestinal compartment, providing a mechanistic link to its protective effects in EAE.

Overexpression of endothelial β4 integrin has no impact on blood-brain barrier integrity or the pathogenesis of experimental autoimmune encephalomyelitis.

Neuroprotective Role of Allopregnanolone in Alleviating Depression-like behaviors by Modulating Brain Function in Experimental Autoimmune Encephalomyelitis Model.

Therapeutic effects of telomerase-derived peptide GV1001 in experimental autoimmune encephalomyelitis: Inhibiting neuroinflammation and promoting remyelination.

The benefit of mineralocorticoid receptor blockade in the treatment of experimental autoimmune encephalomyelitis mice.

Low-molecular weight protamine enhances neuroprotection and remyelination by mitigating chondroitin sulfate proteoglycan inhibition in models of demyelination.

Diagnostic and therapeutic potential of resolvin D1 in Guillain-Barré syndrome.

Neuropathic pain (NP) is one of the most devastating and under-managed symptoms of multiple sclerosis (MS). As it stands, NP is a difficult condition to treat, as many commonly used pain therapies are ineffective. Research has now emerged demonstrating sex differences in the mechanism of NP in MS, adding complexity to the search for new treatments. Although it is widely known that female patients are more likely than male patients to develop MS, it is less commonly acknowledged that they are also more likely to experience NP in the disease. Thus, there is an urgent need to develop NP treatments specifically for female patients with MS. Using the experimental autoimmune encephalomyelitis (EAE) mouse model of MS, we have characterized the outgrowth in culture as well as the spinal innervation pattern of peptidergic primary sensory afferents in both sexes. We then used a receptor antagonist to disrupt neuropeptide signaling from these cells to treat pain. We found structural plasticity in peptidergic nociceptors from female animals with established EAE both in vitro and in vivo, as well as increased antibody stain intensity for the neuropeptide calcitonin gene-related peptide (CGRP). Using a receptor antagonist for CGRP (CGRP8-37), we were able to reverse spontaneous pain in female EAE animals. These results suggest that targeting peptidergic nociceptors and CGRP signaling, specifically in female patients, may be a viable strategy to relieve and possibly reverse pain in female patients with MS.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS), characterized by myelin damage and neurodegeneration. This study focuses on the role of the TRIM37-PEX5 axis in regulating oxidative stress in oligodendrocytes and myelin repair, exploring its potential as a novel therapeutic target for MS. Through bioinformatics analysis, TRIM37 was found to be significantly downregulated in MS patients. In vitro experiments demonstrated that overexpression TRIM37 could stabilize PEX5 protein via non-degradative monoubiquitination, thereby maintaining peroxisomal metabolic function, reducing oxidative stress levels, significantly decreasing apoptosis in both oligodendrocytes and neurons, and promoting the expression of myelin basic protein (MBP). Further mechanistic studies revealed that the TRIM37-PEX5 axis mitigates apoptosis in oligodendrocytes by regulating oxidative stress levels. in vivo experiments further confirmed the neurorestorative effects of TRIM37. In an experimental autoimmune encephalomyelitis (EAE) model, overexpression TRIM37 significantly suppressed neuroinflammation mediated by microglia, reduced the expression of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), and alleviated demyelination lesions (as evidenced by reduced myelin damage shown by Luxol fast blue (LFB) staining, P < 0.001), while simultaneously increasing MBP expression levels (P < 0.001). In conclusion, targeting the TRIM37-PEX5 axis holds promise as a novel strategy for improving myelin damage and providing neuroprotection in MS, offering a theoretical basis for interventions in metabolism-oxidative stress-related diseases.

Multiple sclerosis (MS) is an autoimmune and neuroinflammation disease characterized by axonal damage, inflammatory demyelination, and neurodegeneration. However, the precise mechanisms underlying MS pathogenesis remain largely unclear. Here, we identify ZNRF1, an E3 ubiquitin ligase, as a critical regulator of experimental autoimmune encephalomyelitis (EAE), a murine model that recapitulates the autoimmune demyelination features of MS. Mice lacking ZNRF1 exhibit increased susceptibility to EAE progression. Notably, ZNRF1 depletion in peripheral myeloid cells, but not in microglia, leads to enhanced immune cell infiltration into the central nervous system, resulting in demyelination and exacerbated disease severity. The heightened EAE severity in Znrf1-deficient mice is associated with increased polarization of Th1 and Th17 cells, elevated antigen-specific T helper cell proliferation, and amplified immune responses. Furthermore, following EAE induction, macrophages from Znrf1-deficient mice display elevated surface expression of MHC class II (MHC-II) molecules. Collectively, our findings suggest that ZNRF1 in peripheral myeloid cells plays a suppressive role in neuroinflammation by regulating MHC-II surface expression, thereby controlling antigen-specific T-cell proliferation and activation.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12974-025-03550-z.

The presence of neural stem cells (NSCs) of the subventricular and subgranular zone in the adult mammalian brain has been the focus of much attention; however, these high-function centers have low regenerative ability in response to brain damage. In this review, we focus on the mediobasal hypothalamus (MBH)-a diencephalic region lining the floor of the third ventricle-and the medulla oblongata, a brainstem structure. Both contain niche-like glial populations with context-dependent neurogenic and gliogenic potential. These evolutionarily conserved regions contain neural circuits essential for life support and display high regenerative capacity in lower vertebrates. Recently, NSCs and neural progenitor cells (NPCs) have been reported in the MBH, including the arcuate nucleus and median eminence. Mediobasal hypothalamic tanycytes, with proximal cell bodies facing the third ventricle and distal cellular processes toward the parenchyma, are identified as NSCs that supply various progenitor and ependymal cells. Neural circuits of the MBH exhibit relatively regenerative capability with near-complete or alternative neuronal circuit reorganization after hypothalamic neuronal damage. In the medulla oblongata, there are two types of NSCs: astrocyte-like NSCs in the area postrema and tanycyte-like NSCs in the central canal facing the cerebrospinal fluid. Astrocyte-like NSCs exhibit relatively active proliferation, whereas tanycyte-like NSCs are almost quiescent. Monosodium glutamate selectively induces neuronal cell death in the area postrema, and NPCs proliferate and differentiate into mature neurons, resulting in near-complete restoration of neuronal density. Experimental autoimmune encephalomyelitis causes demyelination in the medulla oblongata, and NSCs partially restore the density of oligodendrocytes. Thus, recent studies indicate that the adult MBH and medulla oblongata exhibit context-dependent regenerative responses, supplying new neurons and oligodendrocytes in response to brain damage.

Astrocytes are central to the pathogenesis of multiple sclerosis (MS); however, their regulation by post-translational ubiquitination and deubiquitination is unresolved. This study shows that the deubiquitinating enzyme OTUD7B in astrocytes protects against murine experimental autoimmune encephalomyelitis (EAE), a model of MS, by limiting neuroinflammation. RNA-sequencing of isolated astrocytes and spatial transcriptomics show that in EAE, OTUD7B downregulates chemokine expression in astrocytes of inflammatory lesions, which is associated with reduced recruitment of encephalitogenic CD4+ T cells. Furthermore, OTUD7B is necessary for glial fibrillary acidic protein (GFAP) expression of astrocytes bordering inflammatory lesions. Mechanistically, OTUD7B (i) restricts TNF-induced chemokine production of astrocytes by sequential K63- and K48-deubiquitination of RIPK1, which limits NF-κB and MAPK activation and (ii) enables GFAP protein expression by supporting GFAP mRNA expression and preventing its proteasomal degradation through K48-deubiquitination of GFAP. This dual action on TNF signaling and GFAP identifies OTUD7B as a central inhibitor of astrocyte-mediated inflammation.

Sialic acids are widely distributed monosaccharides in the central nervous system (CNS), where they are predominantly found as terminal sialic acid residues, as well as in di-, oligo-, and polysialic forms on the glycocalyx, collectively contributing to the development, resilience, and long-term integrity of the CNS. Harnessing sialic acid–binding immunoglobulin-like lectin (Siglec) receptors by α2.8-linked polysialic acids has been shown to modulate immune responses. In this study, murine and human monocytes were exposed to α2.8-linked low molecular weight polysialic acid (α2.8-polySIA) in vitro, followed by phenotypic, functional, and transcriptomic analyses using flow cytometry and RNA sequencing; therapeutic efficacy was assessed in mice with experimental autoimmune encephalomyelitis (EAE), a pre-clinical model of multiple sclerosis (MS). Here, we report that α2.8-polySIA inhibits toll-like receptor-induced phenotypical and functional maturation of murine and human monocytes into pro-inflammatory effector cells equipped with operational antigen-presenting machinery. Moreover, RNA sequencing analyses revealed a shift towards a regulatory phenotype in human myeloid cells exposed to α2.8-polySIA. Finally, therapeutic treatment with α2.8-polySIA led to a milder disease course in EAE mice. Thus, by tuning myeloid cell phenotype in vivo, the therapeutic application of polysialic acid may offer a novel approach to modulate myeloid-driven inflammation in CNS autoimmunity.

Mycobacterium tuberculosis (Mtb) effectively suppresses host immunity to ensure its survival. We have earlier shown that the Acr1 protein of Mtb can inhibit the differentiation of dendritic cells (DCs). Consequently, in the current study, we examined the role of Acr1 in mitigating autoimmunity. Initially, we observed that Acr1 skews the differentiation of DCs into functionally competent myeloid-derived suppressor cells (MDSCAcr1) that chiefly secrete immunosuppressive molecules, expand regulatory T cells (TregAcr1) and attenuate inflammatory responses. Further, MDSCAcr1 suppress Th17 cells. Acr1 expanded MDSCs with a concurrent increase in myelin oligodendrocyte glycoprotein (MOG)-specific Tregs and a decline in Th17 cells in a murine experimental autoimmune encephalomyelitis (EAE) model and prevented the onset of the disease. These results were further validated in the prophylactic model of EAE. Mechanistically, Acr1 activates Tregs and MDSCs via the TLR-4 pathway, implicating innate immune recognition in Mtb-induced suppression. The results indicate a potential role of Acr1 against autoimmune diseases.

Context: Multiple sclerosis (MS) is a multifaceted neurological condition characterized by the demyelination and inflammation of the central nervous system (CNS), predominantly caused by autoimmune reactions targeting myelin antigens. The animal model known as experimental autoimmune encephalomyelitis (EAE) has played a crucial role in elucidating the fundamental mechanisms associated with MS. Evidence Acquisition: Research using EAE has revealed that inflammatory processes, oxidative stress, axonal degeneration, apoptosis, and subsequent demyelination play significant roles in the disease's pathology. The management of MS symptoms involves a combination of pharmacological and non-pharmacological strategies. Among the various therapeutic agents being explored, crocin, a water-soluble carotenoid known for its pharmacological properties, has garnered considerable attention. Results: Crocin has been extensively investigated for its anti-apoptotic, anti-inflammatory, and antioxidant effects, particularly in the context of neurodegenerative diseases. Recent studies have highlighted the potential therapeutic benefits of crocin for MS patients. Conclusions: In this review, we summarize the positive effects of crocin on various deficits observed in MS and EAE, providing insights into its role as a promising adjunct therapy in the management of these neurological disorders.

Stimulator of interferon genes (STING) is a cytosolic DNA sensor that activates type I interferon (IFN) signaling, which plays a key role in neuroinflammation. Although the role of STING in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), remains debated, its involvement in the development of CNS lesions, particularly within localized pathology, modeled here by targeting the corpus callosum, has yet to be explored. Using a focal EAE model, we compared the induction of lesions in wild-type and STING-deficient (STINGgt/gt) mice. Lesions were analyzed by immunohistochemistry, flow cytometry, and transcriptomics. STING-deficient mice had significantly larger demyelinated lesions, reduced ISG expression, and modified immune cell infiltration. STING signaling limits lesion severity in focal EAE by promoting IFN responses and regulating immune infiltration. These findings position STING as a potential target for MS therapy.

Women are more susceptible to multiple sclerosis (MS) than men, with a reported incidence ratio of ~3:1. Kdm6a is an X-chromosomal gene that escapes X inactivation, leading to higher expression of the histone demethylase KDM6A in females compared with males. Here, we focused on the role of Kdm6a in microglia in MS because this cell type plays a key role in the neuropathology of MS. Kdm6a was selectively deleted from microglia in experimental autoimmune encephalomyelitis (EAE) mice, an established model of MS. Deletion of Kdm6a in microglia ameliorated pathology, reduced the expression of disease-associated markers, increased the expression of resting microglial markers, and reversed other translatome changes in spinal cord tissues of female EAE mice. Deletion of Kdm6a in microglia had only very minor effects on EAE in male mice. The diabetes medicine metformin, which also blocks KDM6A's histone demethylase activity, ameliorated EAE in females, but not males, and normalized translatome profiles in microglia. CUT&RUN and sequencing analysis of microglial nuclei identified genes bound by KDM6A. When combined with translatomic analysis, this revealed correspondence between KDM6A protein binding and gene expression changes. Transcriptomic analysis of human microglia confirmed the higher expression of KDM6A in women compared with men and revealed that more microglial genes were dysregulated in women than in men with MS. Our results suggest that KDM6A might contribute to sex differences in susceptibility to MS.

Multiple sclerosis (MS) is a progressive, chronic, and highly disabling neuroinflammatory disorder characterized by demyelination and T cell–driven inflammation. Pathogenic T cells play a central role in MS, but effective therapeutic targeting remains challenging. Here, we identified ankyrin repeat domain–containing protein 55 (ANKRD55) as a key regulator of T cell function by single-cell transcriptomic analysis of cerebrospinal fluid and blood from MS patients. ANKRD55 was predominantly expressed in CD4+ T cells in both compartments. Genetic ablation of Ankrd55 led to a robustly reduced disease severity and neuroinflammation in experimental autoimmune encephalomyelitis (EAE), a widely used animal model for MS. Furthermore, T cell–specific deficiency of Ankrd55 significantly impaired Th1 polarization and Th17 differentiation, reducing EAE pathogenicity. Mechanistically, we found that Ankrd55 deficiency disrupted T cell receptor (TCR) signaling integrity. We demonstrated that ANKRD55 regulates the formation of the immune synapse, an essential prerequisite for TCR activation, by interacting with subunits of the chaperonin-containing TCP1 (CCT) complex and modulating its activity, enhancing its assembly by competing with CCT5 for binding to TCP1, CCT3, and CCT6. This facilitates proper microtubule organization and TCR activation. These findings establish ANKRD55 as a critical regulator of TCR signaling and highlight its therapeutic potential in pathogenic T cell–driven autoimmune diseases.

Identification of novel SIRT1 up-regulators using a cell-based high-throughput screening assay.