Deferoxamine preconditioning of canine stem cell derived extracellular vesicles alleviates inflammation in an EAE mouse model through STAT3 regulation.

Extracellular vesicles (EVs) from mesenchymal stem cells (MSCs), specifically those preconditioned with deferoxamine (DFO) in canine adipose tissue-derived MSCs (cAT-MSCs), were explored for treating autoimmune diseases. This study assessed the effects of DFO-preconditioned EVs (EVDFO) in an experimental autoimmune encephalomyelitis (EAE) mouse model. cAT-MSCs were treated with DFO for 48 h, after which EVs were isolated. EAE mice received intranasal EV or EVDFO treatments and were euthanized following histopathologic analysis; RNA and protein expression levels were measured. Histologically, EV and EVDFO groups showed a significant reduction in inflammatory cell infiltration and demyelination. Immunofluorescence revealed increased CD206 and Foxp3 expression, indicating elevated M2 macrophages and regulatory T (Treg) cells, particularly in the EVDFO group. Treg cells also notably increased in the spleen of EVDFO -treated mice. STAT3 and pSTAT3 proteins were upregulated in the EAE groups compared to the naïve group. However, following EV treatment, STAT3 expression decreased compared to the EAE group, whereas pSTAT3 expression was similar in both the EV and EAE groups. In conclusion, EVDFO treatment resulted in reduced STAT3 expression, suggesting its role in T cell regulation and the potential of EVDFO in modulating the STAT3 pathway for reducing inflammation more effectively than non-preconditioned EVs.

Correlation of Visual System Biomarkers With Motor Deficits in Experimental Autoimmune Encephalomyelitis-Optic Neuritis.

Purpose: Experimental autoimmune encephalomyelitis (EAE) scoring, the most commonly used primary outcome metric for an in vivo model of multiple sclerosis (MS), is highly variable and subjective. Here we explored the use of visual biomarkers in EAE as more objective and clinically relevant primary outcomes. Methods: Motor impairment in myelin oligodendrocyte glycoprotein-immunized C57BL/6J mice was quantified using a five-point EAE grading scale. Pattern electroretinography (pERG) and retinal ganglion cell/inner plexiform layer (RGC/IPL) complex thickness were measured 60 days after induction. Optic nerve histopathology was analyzed at endpoint. Results: EAE mice displayed motor impairments ranging from mild to severe. Significant correlations were seen between pERG amplitude and last EAE score, mean EAE score, and cumulative EAE score. Optical coherence tomography (OCT) analysis demonstrated a significant correlation between thinning of the RGC/IPL complex and both EAE score and pERG amplitude. Optic nerve histopathology showed significant correlations between demyelination and cumulative EAE score, pERG amplitude, and RGC/IPL complex thickness, as well as between immune cell infiltration and cumulative EAE score, pERG amplitude, and RGC/IPL complex thickness in EAE mice. Conclusions: Unlike EAE scoring, pERG and OCT show direct measurement of retinal structure and function. Therefore we conclude that visual outcomes are well suited as a direct assessment of optic nerve involvement in this EAE model of MS while also being indicative of motor impairment. Translational Relevance: Standardizing directly translatable measurements as primary outcome parameters in the murine EAE model could lead to more rapid and relevant testing of new therapeutic approaches for mitigating MS.

Siponimod treatment response shows partial BDNF dependency in multiple sclerosis models.

So far, only a small number of medications are effective in progressive multiple sclerosis (MS). The sphingosine-1-phosphate-receptor (S1PR)-1,5 modulator siponimod, licensed for progressive MS, is acting both on peripheral immune cells and in the central nervous system (CNS). So far it remains elusive, whether those effects are related to the neurotrophin brain derived neurotrophic factor (BDNF). We hypothesized that BDNF in immune cells might be a prerequisite to reduce disease activity in experimental autoimmune encephalomyelitis (EAE) and prevent neurotoxicity. MOG35-55 immunized wild type (WT) and BDNF knock-out (BDNFko) mice were treated with siponimod or vehicle and scored daily in a blinded manner. Immune cell phenotyping was performed via flow cytometry. Immune cell infiltration and demyelination of spinal cord were assessed using immunohistochemistry. In vitro, effects on neurotoxicity and mRNA regulation were investigated using dorsal root ganglion cells incubated with EAE splenocyte supernatant. Siponimod led to a dose-dependent reduction of EAE scores in chronic WT EAE. Using a suboptimal dosage of 0.45 µg/day, siponimod reduced clinical signs of EAE independent of BDNF-expression in immune cells in accordance with reduced infiltration and demyelination. Th and Tc cells in secondary lymphoid organs were dose-dependently reduced, paralleled with an increase of regulatory T cells. In vitro, neuronal viability trended towards a deterioration after incubation with EAE supernatant; siponimod showed a slight rescue effect following treatment of WT splenocytes. Neuronal gene expression for CCL2 and CX3CL1 was elevated after incubation with EAE supernatant, which was reversed after siponimod treatment for WT, but not for BNDFko. Apoptosis markers and alternative death pathways were not affected. Siponimod exerts both anti-inflammatory and neuroprotective effects, partially related to BDNF-expression. This might in part explain effectiveness during progression in MS and could be a target for therapy.

Circulating platelets modulate oligodendrocyte progenitor cell differentiation during remyelination.

Revealing unknown cues that regulate oligodendrocyte progenitor cell (OPC) function in remyelination is important to optimise the development of regenerative therapies for multiple sclerosis (MS). Platelets are present in chronic non-remyelinated lesions of MS and an increase in circulating platelets has been described in experimental autoimmune encephalomyelitis (EAE) mice, an animal model for MS. However, the contribution of platelets to remyelination remains unexplored. Here we show platelet aggregation in proximity to OPCs in areas of experimental demyelination. Partial depletion of circulating platelets impaired OPC differentiation and remyelination, without altering blood-brain barrier stability and neuroinflammation. Transient exposure to platelets enhanced OPC differentiation in vitro, whereas sustained exposure suppressed this effect. In a mouse model of thrombocytosis (Calr+/-), there was a sustained increase in platelet aggregation together with a reduction of newly-generated oligodendrocytes following toxin-induced demyelination. These findings reveal a complex bimodal contribution of platelet to remyelination and provide insights into remyelination failure in MS.

GV-971 attenuates the progression of neuromyelitis optica in murine models and reverses alterations in gut microbiota and associated peripheral abnormalities.

AIMS: Growing evidence suggests that an imbalanced gut microbiota composition plays a crucial role in the development of neuromyelitis optica spectrum disorders (NMOSD), an inflammatory demyelinating disease primarily affecting the optic nerves and central nervous system (CNS). In light of this, we explored the potential therapeutic benefits of GV-971 in NMOSD. GV-971 is a drug used for treating mild-to-moderate Alzheimer's disease, which targets the gut-brain axis and reduces neuroinflammation. METHODS: To evaluate GV-971's effects, we employed the experimental autoimmune encephalomyelitis (EAE) mouse model to establish NMOSD animal models. This was achieved by injecting NMO-IgG into aged mice (11 months old) or using NMO-IgG along with complement injection and microbubble-enhanced low-frequency ultrasound (MELFUS) techniques in young mice (7 weeks old). We assessed the impact of GV-971 on incidence rate, clinical scores, body weight, and survival, with methylprednisolone serving as a positive control. In NMOSD models of young mice, we analyzed spinal cord samples through H&E staining, immunohistochemistry, and Luxol Fast Blue staining. Fecal samples collected at different time points underwent 16S rRNA gene sequencing, while plasma samples were analyzed using cytokine array and untargeted metabolomics analysis. RESULTS: Our findings indicated that GV-971 significantly reduced the incidence of NMOSD, alleviated symptoms, and prolonged survival in NMOSD mouse models. The NMOSD model exhibited substantial neuroinflammation and injury, accompanied by imbalances in gut microbiota, peripheral inflammation, and metabolic disorders, suggesting a potentially vicious cycle that accelerates disease pathogenesis. Notably, GV-971 effectively reduces neuroinflammation and injury, and restores gut microbiota composition, as well as ameliorates peripheral inflammation and metabolic disorders. CONCLUSIONS: GV-971 attenuates the progression of NMOSD in murine models and reduces neuroinflammation and injury, likely through its effects on remodeling gut microbiota and peripheral inflammation and metabolic disorders.

Asymptomatic herpes simplex virus brain infection elicits cellular senescence phenotypes in the central nervous system of mice suffering multiple sclerosis-like disease.

Experimental autoimmune encephalomyelitis (EAE) is a demyelinating disease affecting the central nervous system (CNS) in animals that parallels several clinical and molecular traits of multiple sclerosis in humans. Herpes simplex virus type 1 (HSV-1) infection mainly causes cold sores and eye diseases, yet eventually, it can also reach the CNS, leading to acute encephalitis. Notably, a significant proportion of healthy individuals are likely to have asymptomatic HSV-1 brain infection with chronic brain inflammation due to persistent latent infection in neurons. Because cellular senescence is suggested as a potential factor contributing to the development of various neurodegenerative disorders, including multiple sclerosis, and viral infections may induce a premature senescence state in the CNS, potentially increasing susceptibility to such disorders, here we examine the presence of senescence-related markers in the brains and spinal cords of mice with asymptomatic HSV-1 brain infection, EAE, and both conditions. Across all scenarios, we find a significant increases of senescence biomarkers in the CNS with some differences depending on the analyzed group. Notably, some senescence biomarkers are exclusively observed in mice with the combined conditions. These results indicate that asymptomatic HSV-1 brain infection and EAE associate with a significant expression of senescence biomarkers in the CNS.

Current Knowledge about Nonclassical Monocytes in Patients with Multiple Sclerosis, a Systematic Review.

Monocytes play a critical role in the initiation and progression of multiple sclerosis (MS). Recent research indicates the importance of considering the roles of monocytes in the management of MS and the development of effective interventions. This systematic review examined published research on the roles of nonclassical monocytes in MS and how they influence disease management. Reputable databases, such as PubMed, EMBASE, Cochrane, and Google Scholar, were searched for relevant studies on the influence of monocytes on MS. The search focused on studies on humans and patients with experimental autoimmune encephalomyelitis (EAE) published between 2014 and 2024 to provide insights into the study topic. Fourteen articles that examined the role of monocytes in MS were identified; the findings reported in these articles revealed that nonclassical monocytes could act as MS biomarkers, aid in the development of therapeutic interventions, reveal disease pathology, and improve approaches for monitoring disease progression. This review provides support for the consideration of monocytes when researching effective diagnostics, therapeutic interventions, and procedures for managing MS pathophysiology. These findings may guide future research aimed at gaining further insights into the role of monocytes in MS.

SWI/SNF chromatin remodeling factor BAF60b restrains inflammatory diseases by affecting regulatory T cell migration.

Regulatory T (Treg) cells play a critical regulatory role in the immune system by suppressing excessive immune responses and maintaining immune balance. The effective migration of Treg cells is crucial for controlling the development and progression of inflammatory diseases. However, the mechanisms responsible for directing Treg cells into the inflammatory tissue remain incompletely elucidated. In this study, we identified BAF60b, a subunit of switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complexes, as a positive regulator of Treg cell migration that inhibits the progression of inflammation in experimental autoimmune encephalomyelitis (EAE) and colitis animal models. Mechanistically, transcriptome and genome-wide chromatin-landscaped analyses demonstrated that BAF60b interacts with the transcription factor RUNX1 to promote the expression of CCR9 on Treg cells, which in turn affects their ability to migrate to inflammatory tissues. Our work provides insights into the essential role of BAF60b in regulating Treg cell migration and its impact on inflammatory diseases.

Synergistic Targeting of Innate Receptors TLR7 and NOD2 for Therapeutic Intervention in Multiple Sclerosis.

Regulation of neuroinflammation is critical for maintaining central nervous system (CNS) homeostasis and holds therapeutic promise in autoimmune diseases such as multiple sclerosis (MS). Previous studies have highlighted the significance of selective innate signaling in triggering anti-inflammatory mechanisms, which play a protective role in an MS-like disease, experimental autoimmune encephalomyelitis (EAE). However, the individual intra-CNS administration of specific innate receptor ligands or agonists, such as for toll-like receptor 7 (TLR7) and nucleotide-binding oligomerization-domain-containing protein 2 (NOD2), failed to elicit the desired anti-inflammatory response in EAE. In this study, we investigated the potential synergistic effect of targeting both TLR7 and NOD2 simultaneously to prevent EAE progression. Our findings demonstrate that simultaneous intrathecal administration of NOD2- and TLR7-agonists led to synergistic induction of Type I IFN (IFN I) and effectively suppressed EAE in an IFN I-dependent manner. Suppression of EAE was correlated with a significant decrease in the infiltration of monocytes, granulocytes, and natural killer cells, reduced demyelination, and downregulation of IL-1ß, CCL2, and IFNγ gene expression in the spinal cord. These results underscore the therapeutic promise of concurrently targeting the TLR7 and NOD2 pathways in alleviating neuroinflammation associated with MS, paving the way for novel and more efficacious treatment strategies.

Short-chain fatty acids suppresses astrocyte activation by amplifying Trp-AhR-AQP4 signaling in experimental autoimmune encephalomyelitis mice.

The function of astrocytes in response to gut microbiota-derived signals has an important role in the pathophysiological processes of central nervous system (CNS) diseases. However, the specific effects of microbiota-derived metabolites on astrocyte activation have not been elucidated yet. Experimental autoimmune encephalomyelitis (EAE) was induced in female C57BL/6 mice as a classical MS model. The alterations of gut microbiota and the levels of short-chain fatty acids (SCFAs) were assessed after EAE induction. We observed that EAE mice exhibit low levels of Allobaculum, Clostridium_IV, Clostridium_XlVb, Lactobacillus genera, and microbial-derived SCFAs metabolites. SCFAs supplementation suppressed astrocyte activation by increasing the level of tryptophan (Trp)-derived AhR ligands that activating the AhR. The beneficial effects of SCFAs supplementation on the clinical scores, histopathological alterations, and the blood brain barrier (BBB)-glymphatic function were abolished by intracisterna magna injection of AAV-GFAP-shAhR. Moreover, SCFAs supplementation suppressed the loss of AQP4 polarity within astrocytes in an AhR-dependent manner. Together, SCFAs potentially suppresses astrocyte activation by amplifying Trp-AhR-AQP4 signaling in EAE mice. Our study demonstrates that SCFAs supplementation may serve as a viable therapy for inflammatory disorders of the CNS.

Cellular Therapy in Experimental Autoimmune Encephalomyelitis as an Adjuvant Treatment to Translate for Multiple Sclerosis.

This study aims to evaluate and compare cellular therapy with human Wharton's jelly (WJ) mesenchymal stem cells (MSCs) and neural precursors (NPs) in experimental autoimmune encephalomyelitis (EAE), a preclinical model of Multiple Sclerosis. MSCs were isolated from WJ by an explant technique, differentiated to NPs, and characterized by cytometry and immunocytochemistry analysis after ethical approval. Forty-eight rats were EAE-induced by myelin basic protein and Freund's complete adjuvant. Forty-eight hours later, the animals received intraperitoneal injections of 250 ng/dose of Bordetella pertussis toxin. Fourteen days later, the animals were divided into the following groups: a. non-induced, induced: b. Sham, c. WJ-MSCs, d. NPs, and e. WJ-MSCs plus NPs. 1 × 105. Moreover, the cells were placed in a 10 µL solution and injected via a stereotaxic intracerebral ventricular injection. After ten days, the histopathological analysis for H&E, Luxol, interleukins, and CD4/CD8 was carried out. Statistical analyses demonstrated a higher frequency of clinical manifestation in the Sham group (15.66%) than in the other groups; less demyelination was seen in the treated groups than the Sham group (WJ-MSCs, p = 0.016; NPs, p = 0.010; WJ-MSCs + NPs, p = 0.000), and a lower cellular death rate was seen in the treated groups compared with the Sham group. A CD4/CD8 ratio of <1 showed no association with microglial activation (p = 0.366), astrocytes (p = 0.247), and cell death (p = 0.577) in WJ-MSCs. WJ-MSCs and NPs were immunomodulatory and neuroprotective in cellular therapy, which would be translated as an adjunct in demyelinating diseases.

Loss of Cells in the Retinal Ganglion Cell Layer as an Early Indication of Neurodegeneration in Multiple Sclerosis.

BACKGROUND: Multiple Sclerosis (MS) is a debilitating neurological disease affecting the central nervous system and significantly impacting patients' quality of life. MS is known as an autoimmune disease affecting the white matter. The disease involves inflammation, demyelination, and neurodegeneration, causing irreversible disabilities. Current treatments for MS target the inflammatory phase, with limited effects on long-term disability. While neuronal damage significantly contributes to MS pathology, mechanisms of neurodegeneration are not well studied. METHODS: This study evaluated neurodegenerative changes in the retina during disease progression, using data collected from an experimental MS model (Experimental Autoimmune Encephalomyelitis, EAE). Utilizing Hematoxylin and Eosin-stained retinal sections and assessment using Optical Coherence Tomography (OCT), the study investigated the neurodegenerative changes, such as loss of cells in the retinal ganglion cell layer (GCL) and retinal thinning in the retina of the EAE model and the control groups. RESULTS: Our results showed a significant reduction in the number of cells in the GCL of the EAE retina at two different time points studied, suggesting loss of neurons compared to the control group. Thickness measurements showed a reduction in the total retina and inner retinal layer thicknesses in the EAE retina compared to the controls. Our results indicate evidence of neurodegenerative changes in the retina of the experimental model of MS. No significant differences were observed between the percent losses of cells between the two time points studied. The pattern of cell loss suggests that neurodegeneration occurs at an earlier stage of disease progression. CONCLUSIONS: Overall, the retina is an excellent model to investigate neurodegeneration in MS, and possibly, loss of cells in the GCL could be used as an early indicator of neurodegeneration in MS and to identify novel therapeutic agents to treat the disease.

2-Bromo-1,4-Naphthalenedione promotes CD8+ T cell expansion and limits Th1/Th17 to mitigate experimental autoimmune encephalomyelitis.

Treating Multiple sclerosis (MS), a well-known immune-mediated disease characterized by axonal demyelination, is challenging due to its complex causes. Naphthalenedione, present in numerous plants, is being explored as a potential medicine for MS due to its immunomodulatory properties. However, its effects on lymphocytes can vary depending on factors such as the specific compound, concentration, and experimental conditions. In this study, we aim to explore the therapeutic potential of 2-bromo-1,4-naphthalenedione (BrQ), a derivative of naphthalenedione, in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, and to elucidate its underlying mechanisms. We observed that mice treated with BrQ exhibited reduced severity of EAE symptoms, including lower clinical scores, decreased leukocyte infiltration, and less extensive demyelination in central nervous system. Furthermore, it was noted that BrQ does not directly affect the remyelination process. Through cell-chat analysis based on bulk RNA-seq data, coupled with validation of flow analysis, we discovered that BrQ significantly promotes the expansion of CD8+ T cells and their interactions with other immune cells in peripheral immune system in EAE mice. Subsequent CD8+ T cell depletion experiments confirmed that BrQ alleviates EAE in a CD8+ T cell-dependent manner. Mechanistically, expanded CD8+ cells were found to selectively reduce antigen-specific CD4+ cells and subsequently inhibit Th1 and Th17 cell development in vivo, ultimately leading to relief from EAE. In summary, our findings highlight the crucial role of BrQ in modulating the pathogenesis of MS, suggesting its potential as a novel drug candidate for treating MS and other autoimmune diseases.

Differences in the characteristics and functions of brain and spinal cord regulatory T cells.

T cells play an important role in the acquired immune response, with regulatory T cells (Tregs) serving as key players in immune tolerance. Tregs are found in nonlymphoid and damaged tissues and are referred to as "tissue Tregs". They have tissue-specific characteristics and contribute to immunomodulation, homeostasis, and tissue repair through interactions with tissue cells. However, important determinants of Treg tissue specificity, such as antigen specificity, tissue environment, and pathology, remain unclear. In this study, we analyzed Tregs in the central nervous system of mice with ischemic stroke and experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. The gene expression pattern of brain Tregs in the EAE model was more similar to that of ischemic stroke Tregs in the brain than to that of spinal cord Tregs. In addition, most T-cell receptors (TCRs) with high clonality were present in both the brain and spinal cord. Furthermore, Gata3+ and Rorc+ Tregs expressed TCRs recognizing MOG in the spinal cord, suggesting a tissue environment conducive to Rorc expression. Tissue-specific chemokine/chemokine receptor interactions in the spinal cord and brain influenced Treg localization. Finally, spinal cord- or brain-derived Tregs had greater anti-inflammatory capacities in EAE mice, respectively. Taken together, these findings suggest that the tissue environment, rather than pathogenesis or antigen specificity, is the primary determinant of the tissue-specific properties of Tregs. These findings may contribute to the development of novel therapies to suppress inflammation through tissue-specific Treg regulation.

Spontaneous human CD8 T cell and autoimmune encephalomyelitis-induced CD4/CD8 T cell lesions in the brain and spinal cord of HLA-DRB1*15-positive multiple sclerosis humanized immune system mice.

Autoimmune diseases of the central nervous system (CNS) such as multiple sclerosis (MS) are only partially represented in current experimental models and the development of humanized immune mice is crucial for better understanding of immunopathogenesis and testing of therapeutics. We describe a humanized mouse model with several key features of MS. Severely immunodeficient B2m-NOG mice were transplanted with peripheral blood mononuclear cells (PBMCs) from HLA-DRB1-typed MS and healthy (HI) donors and showed rapid engraftment by human T and B lymphocytes. Mice receiving cells from MS patients with recent/ongoing Epstein-Barr virus reactivation showed high B cell engraftment capacity. Both HLA-DRB1*15 (DR15) MS and DR15 HI mice, not HLA-DRB1*13 MS mice, developed human T cell infiltration of CNS borders and parenchyma. DR15 MS mice uniquely developed inflammatory lesions in brain and spinal cord gray matter, with spontaneous, hCD8 T cell lesions, and mixed hCD8/hCD4 T cell lesions in EAE immunized mice, with variation in localization and severity between different patient donors. Main limitations of this model for further development are poor monocyte engraftment and lack of demyelination, lymph node organization, and IgG responses. These results show that PBMC humanized mice represent promising research tools for investigating MS immunopathology in a patient-specific approach.

Characterization of spinal cord tissue-derived extracellular vesicles in neuroinflammation.

Extracellular vesicles (EVs) are released by all cells, can cross the blood-brain barrier, and have been shown to play an important role in cellular communication, substance shuttling, and immune modulation. In recent years EVs have shifted into focus in multiple sclerosis (MS) research as potential plasma biomarkers and therapeutic vehicles. Yet little is known about the disease-associated changes in EVs in the central nervous system (CNS). To address this gap, we characterized the physical and proteomic changes of mouse spinal cord-derived EVs before and at 16 and 25 days after the induction of experimental autoimmune encephalomyelitis (EAE), a neuroinflammatory model of MS. Using various bioinformatic tools, we found changes in inflammatory, glial, and synaptic proteins and pathways, as well as a shift in the predicted contribution of immune and glial cell types over time. These results show that EVs provide snapshots of crucial disease processes such as CNS-compartmentalized inflammation, re/de-myelination, and synaptic pathology, and might also mediate these processes. Additionally, inflammatory plasma EV biomarkers previously identified in people with MS were also altered in EAE spinal cord EVs, suggesting commonalities of EV-related pathological processes during EAE and MS and overlap of EV proteomic changes between CNS and circulating EVs.

Fluorinated apelin-13 mediates neuroprotective effects in multiple sclerosis models.

Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease leading to demyelination and axonal loss. Current treatments are immunomodulatory or immunosuppressive drugs acting on the inflammatory component. However, these treatments do not adequately address the crucial aspect of neuroprotection. Recently, an association between an altered balance of adipokines and MS has been proposed as both a risk factor for developing MS and a chronic disease aggravating factor. Specifically, a decrease of apelin plasma levels in MS patients compared to controls correlates with the number of relapses and disease severity. Here we report a dramatic downregulation of apelin levels in the CNS of EAE mice which is also detected in MS patients brain samples compared to controls. Exploiting innovative design and synthesis techniques, we engineered a novel fluorinated apelin-13 peptide characterized by enhanced plasmatic stability compared to its native counterpart. With this peptide, we assessed the potential therapeutic benefits of apelin preventive supplementation in the EAE mouse model. We show that the fluorinated Apelin-13 peptide ameliorates EAE clinical score and preserves myelin content in the EAE MOG model recapitulating the progressive form of disease. These results combined with ex-vivo experiments in brain organotypic slices and in vitro studies in neurons and primary microglia and macrophages suggest that apelin has neuroprotective effects and influences the microglia/macrophages function.

Myelin oligodendrocyte glycoprotein reactive Th17 cells drive Janus Kinase 1 dependent transcriptional reprogramming in astrocytes and alter cell surface cytokine receptor profiles during experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is an autoimmune demyelinating disease affecting the central nervous system (CNS). T helper (Th) 17 cells are involved in the pathogenesis of MS and its animal model of experimental autoimmune encephalomyelitis (EAE) by infiltrating the CNS and producing effector molecules that engage resident glial cells. Among these glial cells, astrocytes have a central role in coordinating inflammatory processes by responding to cytokines and chemokines released by Th17 cells. In this study, we examined the impact of pathogenic Th17 cells on astrocytes in vitro and in vivo. We identified that Th17 cells reprogram astrocytes by driving transcriptomic changes partly through a Janus Kinase (JAK)1-dependent mechanism, which included increased chemokines, interferon-inducible genes, and cytokine receptors. In vivo, we observed a region-specific heterogeneity in the expression of cell surface cytokine receptors on astrocytes, including those for IFN-γ, IL-1, TNF-α, IL-17, TGFß, and IL-10. Additionally, these receptors were dynamically regulated during EAE induced by adoptive transfer of myelin-reactive Th17 cells. This study overall provides evidence of Th17 cell reprogramming of astrocytes, which may drive changes in the astrocytic responsiveness to cytokines during autoimmune neuroinflammation.

Animal model of multiple sclerosis: Experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is a very complex and heterogeneous disease, with an unknown etiology and which, currently, remains incurable. For this reason, animal models are crucial to investigate this disease, which has increased in prevalence in recent years, affecting 2.8 million people worldwide, and is the leading cause of non-traumatic disability in young adults between the ages of 20-30years. Of all the models developed to replicate MS, experimental autoimmune encephalomyelitis (EAE) best reflects the autoimmune pathogenesis of MS. There are different methods to induce it, which will give rise to different types of EAE, which will vary in clinical presentation and severity. Of the EAE models, the most widespread and used is the one induced in rodents due to its advantages over other species. Likewise, EAE has become a widely used model in the development of therapies for the treatment of MS. Likewise, it is very useful to define the cellular and molecular mechanisms involved in the pathogenesis of MS and to establish therapeutic targets for this disease. For all these reasons, the EAE model plays a key role in improving the understanding of MS.

JAK2/STAT3 Pathway Inhibition by AG490 Ameliorates Experimental Autoimmune Encephalomyelitis via Regulation of Th17 Cells and Autophagy.

Multiple sclerosis (MS) is an autoimmune inflammatory condition affecting the central nervous system, and experimental autoimmune encephalomyelitis (EAE) animal models have been extensively used to study it. T-helper 17 cells, which produce interleukin-17(IL-17), play crucial roles in MS pathogenesis, and the JAK2/STAT3 pathway has an essential function in their differentiation from naive CD4 + T cells. This study investigated the effects of the JAK2/STAT3 pathway inhibitor AG490 on EAE in vivo and in vitro, as well as the underlying mechanisms. AG490 ameliorated EAE severity and attenuated its typical symptoms by downregulating proteins associated with the JAK2/STAT3 pathway. Furthermore, it decreased T-helper 17 cell differentiation from naive CD4 + T cells by inactivating STAT3. In addition, it conferred protective effects against EAE by restoring autophagy. These findings indicate the potential of AG490 as a candidate anti-MS therapeutic.