Changes in adaptive immunity and increased neuroinflammation are key processes in ageing EAE: a road to develop new therapeutic strategies for elderly MS patients
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE227650 | GEO | 2024/12/01
REPOSITORIES: GEO
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Project description:Changes in adaptive immunity and increased neuroinflammation are key processes in ageing EAE: a road to develop new therapeutic strategies for elderly MS patients
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Project description:The decrease of gelsolin (GSN) in the blood has been reported in multiple sclerosis (MS) patients and experimental allergic encephalomyelitis (EAE) animals, but the protective effect of GSN on EAE/MS lacks of evidence. In our study, we increased the GSN level in EAE by injecting GSN-overexpress lentivirus (LV-GSN) into the lateral ventricle and caudal vein and found that GSN administration can delay the onset and decrease the severity of EAE. Vitamin D is proven to have a therapeutic effect on MS/EAE; however, we previously found that vitamin D caused a downregulation of GSN, which might limit vitamin D efficacy. In our current research, we obtained a better symptom and a slowing down progression in EAE after combining vitamin D treatment with a proper increase of GSN. Furthermore, we discovered that the mediation of vitamin D on GSN might occur through the vitamin D receptor (VDR) by using gene interruption and overexpression to regulate the level of VDR in PC12 cells (a rat sympathetic nerve cell line). We also confirmed the anti-apoptotic function of GSN by GSN RNA interference in PC12. Collectively, these results support the therapeutic effect of GSN in EAE, which might enhance Vitamin D therapy in EAE/MS.
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Project description:Proinflammatory T-lymphocytes recruited into the brain and spinal cord mediate multiple sclerosis (MS) and currently there is no cure for MS. IFN-γ-producing Th1 cells induce ascending paralysis in the spinal cord while IL-17-producing Th17 cells mediate cerebellar ataxia. STAT1 and STAT3 are required for Th1 and Th17 development, respectively, and the simultaneous targeting of STAT1 and STAT3 pathways is therefore a potential therapeutic strategy for suppressing disease in the spinal cord and brain. However, the pharmacological targeting of STAT1 and STAT3 presents significant challenges because of their intracellular localization. We have developed a STAT-specific single-domain nanobody (SBT-100) derived from camelids that targets conserved residues in Src homolog 2 (SH2) domains of STAT1 and STAT3. This study investigated whether SBT-100 could suppress experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. We show that SBT-100 ameliorates encephalomyelitis through suppressing the expansion of Th17 and Th1 cells in the brain and spinal cord. Adoptive transfer experiments revealed that lymphocytes from SBT-100-treated EAE mice have reduced capacity to induce EAE, indicating that the immunosuppressive effects derived from the direct suppression of encephalitogenic T-cells. The small size of SBT-100 makes this STAT-specific nanobody a promising immunotherapy for CNS autoimmune diseases, including multiple sclerosis.
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Project description:Considerable clinical evidence supports that increased blood-brain barrier (BBB) permeability is linked to immune extravasation of CNS parenchyma during neuroinflammation. Although BBB permeability and immune extravasation are known to be provoked by vascular endothelial growth factor-A (i.e., VEGF-A) and C-X-C motif chemokine ligand 12 (CXCL12), respectively, the mechanisms that link both processes are still elusive. The interleukin-20 (i.e., IL-20) cytokine signaling pathway was previously implicated in VEGF-mediated angiogenesis and is known to induce cellular response by way of signaling through IL-20 receptor subunit β (i.e., IL-20RB). Dysregulated IL-20 signaling is implicated in many inflammatory pathologies, but it's contribution to neuroinflammation has yet to be reported. We hypothesize that the IL-20 cytokine, and the IL cytokine subfamily more broadly, play a key role in CNS neuroinflammation by signaling through IL-20RB, induce VEGF activity, and enhance both BBB-permeability and CXCL12-mediated immune extravasation. To address this hypothesis, we actively immunized IL-20RB-/- mice and wild-type mice to induce experimental autoimmune encephalomyelitis (EAE) and found that IL-20RB-/- mice showed amelioration of disease progression compared to wild-type mice. Similarly, we passively immunized IL-20RB-/- mice and wild-type mice with myelin-reactive Th1 cells from either IL-20RB-/- and wild-type genotype. Host IL-20RB-/- mice showed lesser disease progression than wild-type mice, regardless of the myelin-reactive Th1 cells genotype. Using multianalyte bead-based immunoassay and ELISA, we found distinctive changes in levels of pro-inflammatory cytokines between IL-20RB-/- mice and wild-type mice at peak of EAE. We also found detectable levels of all cytokines of the IL-20 subfamily within CNS tissues and specific alteration to IL-20 subfamily cytokines IL-19, IL-20, and IL-24, expression levels. Immunolabeling of CNS region-specific microvessels confirmed IL-20RB protein at the spinal cord microvasculature and upregulation during EAE. Microvessels isolated from macaques CNS tissues also expressed IL-20RB. Moreover, we identified the expression of all IL-20 receptor subunits: IL-22 receptor subunit α-1 (IL-22RA1), IL-20RB, and IL-20 receptor subunit α (IL-20RA) in human CNS microvessels. Notably, human cerebral microvasculature endothelial cells (HCMEC/D3) treated with IL-1β showed augmented expression of the IL-20 receptor. Lastly, IL-20-treated HCMEC/D3 showed alterations on CXCL12 apicobasal polarity consistent with a neuroinflammatory status. This evidence suggests that IL-20 subfamily cytokines may signal at the BBB via IL-20RB, triggering neuroinflammation.
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Project description:Ferroptosis is a form of lipid peroxidation-mediated cell death and damage triggered by excess iron and insufficiency in the glutathione antioxidant pathway. Oxidative stress is thought to play a crucial role in progressive forms of multiple sclerosis (MS) in which iron deposition occurs. In this study we assessed if ferroptosis plays a role in a chronic form of experimental autoimmune encephalomyelitis (CH-EAE), a mouse model used to study MS. Changes were detected in the mRNA levels of several ferroptosis genes in CH-EAE but not in relapsing-remitting EAE. At the protein level, expression of iron importers is increased in the earlier stages of CH-EAE (onset and peak). While expression of hemoxygenase-1, which mobilizes iron from heme, likely from phagocytosed material, is increased in macrophages at the peak and progressive stages. Excess iron in cells is stored safely in ferritin, which increases with disease progression. Harmful, redox active iron is released from ferritin when shuttled to autophagosomes by 'nuclear receptor coactivator 4' (NCOA4). NCOA4 expression increases at the peak and progressive stages of CH-EAE and accompanied by increase in redox active ferrous iron. These changes occur in parallel with reduction in the antioxidant pathway (system xCT, glutathione peroxidase 4 and glutathione), and accompanied by increased lipid peroxidation. Mice treated with a ferroptosis inhibitor for 2 weeks starting at the peak of CH-EAE paralysis, show significant improvements in function and pathology. Autopsy samples of tissue sections of secondary progressive MS (SPMS) showed NCOA4 expression in macrophages and oligodendrocytes along the rim of mixed active/inactive lesions, where ferritin+ and iron containing cells are located. Cells expressing NCOA4 express less ferritin, suggesting ferritin degradation and release of redox active iron, as indicated by increased lipid peroxidation. These data suggest that ferroptosis is likely to contribute to pathogenesis in CH-EAE and SPMS.
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Project description:Manipulation of stem cells or stem cells-derived secretome has emerged as a novel alternative therapeutic option for multiple sclerosis (MS). Here we show that human periodontal ligament stem cells (hPDLSCs)-derived conditioned medium (hPDLSCs-CM) and purified exosomes/microvesicles (hPDLSCs-EMVs) obtained from Relapsing Remitting (RR)-MS patients and healthy donors block experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, by inducing anti-inflammatory and immunosuppressive effects in spinal cord and spleen, and reverse disease progression by restoring tissue integrity via remyelination in the spinal cord. We show that hPDLSCs-CM and hPDLSCs-EMVs reduce pro-inflammatory cytokines IL-17, IFN-γ, IL-1β, IL-6, TNF-α, and induce anti-inflammatory IL-10. In addition, apoptosis related STAT1, p53, Caspase 3, and Bax expressions were attenuated. Our findings unravel the immunosuppressive effects of hPDLSCs-CM and hPDLSCs-EMVs in EAE mice, and suggest simple alternative autologous source for patient-customized cell-free targeting treatment in MS patients.
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Project description:While age-associated B cells (ABCs) are known to expand and persist following viral infection and during autoimmunity, their interactions are yet to be studied together in these contexts. Here, we directly compared CD11c+T-bet+ ABCs using models of Epstein-Barr virus (EBV), gammaherpesvirus 68 (γHV68), multiple sclerosis (MS), and experimental autoimmune encephalomyelitis (EAE), and found that each drives the ABC population to opposing phenotypes. EBV infection has long been implicated in MS, and we have previously shown that latent γHV68 infection exacerbates EAE. Here, we demonstrate that ABCs are required for γHV68-enhanced disease. We then show that the circulating ABC population is expanded and phenotypically altered in people with relapsing MS. In this study, we show that viral infection and autoimmunity differentially affect the phenotype of ABCs in humans and mice, and we identify ABCs as functional mediators of viral-enhanced autoimmunity.
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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:Metazoans gather information from their environments and respond in predictable ways. These computational tasks are achieved with neural networks of varying complexity. Their performance must be reliable over an individual's lifetime while dealing with the shorter lifespan of cells and connection failure-thus rendering ageing a relevant feature. How do computations degrade over an organism's lifespan? How reliable can they remain throughout? We tackle these questions with a multi-objective optimization approach. We demand that digital organisms equipped with neural networks solve a computational task reliably over an extended lifespan. Neural connections are costly (as an associated metabolism in living beings). They also degrade over time, but can be regenerated at some expense. We investigate the simultaneous minimization of both these costs and the computational error. Pareto optimal trade-offs emerge with designs displaying a broad range of solutions: from small networks with high regeneration rate, to large, redundant circuits that regenerate slowly. The organism's lifespan and the external damage act as evolutionary pressures. They improve the exploration of the space of solutions and impose tighter optimality constraints. Large damage rates can also constrain the space of possibilities, forcing the commitment of organisms to unique strategies for neural systems maintenance.
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