Notch3+ Regulatory T cells Drive Autoimmune Neuroinflammation in Multiple Sclerosis
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PROVIDER: PRJNA1066344 | ENA |
REPOSITORIES: ENA
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Project description:The immune regulatory defects that promote neuroinflammation in multiple sclerosis (MS) remain unclear. We show that a specific regulatory T (Treg) cell subpopulation expressing Notch3 is increased in individuals with MS and in mice with experimental autoimmune encephalomyelitis (EAE). Notch3 is induced by the gut microbiota by toll-like receptor (TLR)-dependent mechanisms to promote EAE severity. Notch3 interacts with delta-like ligand 1 (DLL1) on microglia to subvert Treg cells into T helper 17 (Th17) cells. Notch3 Treg-specific deletion inhibits EAE by preventing Treg cell destabilization while simultaneously promoting the expansion of a novel tissue-resident neuropeptide receptor 1 (NPY1R)+ Treg cell population that suppressed pathogenic IFNg+ and GM-CSF+ T cells. Our studies thus identify altered Treg cell population dynamics as a fundamental pathogenic mechanism in autoimmune neuroinflammation.
2025-07-01 | GSE253602 | GEO
Project description:Deciphering the mechanisms that promote central nervous system inflammation in multiple sclerosis is critical for developing precision therapies. We show that a specific regulatory T (Treg) cell subpopulation expressing Notch3 was increased in the peripheral blood and cerebrospinal fluid of individuals with multiple sclerosis (MS) and in the central nervous system (CNS) of mice with experimental autoimmune encephalomyelitis (EAE). Notch3 expression was upregulated by mechanisms involving the gut microbiota and Treg cell-specific toll-like receptor (TLR) signaling to promote EAE severity. Notch3 interaction with delta-like ligand 1 (DLL1) on microglia subverted Treg cells into T helper 17 (Th17) cells by Hippo pathway-dependent mechanisms while also inducing an inflammatory microglial response. Its deletion inhibited EAE by preventing Treg cell destabilization into Th17 cells while simultaneously promoting the expansion of a novel brain-protective neuropeptide receptor 1 (NPY1R)+ Treg cell population that suppressed pathogenic IFN+ and GM-CSF+ effector T cells. Our studies thus identify Notch3-mediated immune tolerance subversion as a fundamental mechanism that licenses autoimmune neuroinflammation.
2025-07-02 | GSE253097 | GEO
Project description:Notch3 Directs a Regulatory T Cells-Microglia axis to Promote Autoimmune Neuroinflammation
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Project description:Oligodendrocyte regulation during autoimmune neuroinflammation
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Project description:The present study had the purpose to analyze the transcriptional state of oligodendrocytes in an animal model of multiple scleroris resembling autoimmune neuroinflammation and compared with control mice treated with ovalbumin. The results revealed that oligodendrocytes from the EAE (experimental autoimmune encephalomyelitis) model upregulate genes that are involved in immune processes providing evidence that oligodendrocytes can develop an immune phenotype in particular neuroinflammatory conditions.
2021-08-21 | GSE182341 | GEO
Project description:Autoimmune diseases such as multiple sclerosis (MS) develop because of failed peripheral immune tolerance for a specific self-antigen (Ag). Numerous approaches for Ag-specific suppression of autoimmune neuroinflammation have been proven in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. One such approach is intravenous (i.v.) tolerance induction by injecting a myelin Ag used for EAE induction. However, the translation of this and similar experimental strategies into therapy for MS has been hampered by uncertainty regarding relevant myelin Ags in MS patients. To address this issue, we developed a therapeutic strategy that relies on oligodendrocyte (Ol)-derived extracellular vesicles (Ol-EVs), which naturally contain multiple myelin Ags. Ol-EVs injected i.v. suppressed disease in a myelin Ag-dependent manner, both prophylactically and therapeutically, in several EAE models. The treatment was safe and restored immune tolerance by inducing immunosuppressive monocytes and apoptosis of autoreactive encephalitogenic CD4+ T cells. Finally, we show that human Ols also release EVs containing most relevant myelin Ags, providing a basis for their use in MS therapy. These findings introduce an approach for suppressing central nervous system autoimmunity in a myelin Ag-specific manner.
2020-05-17 | MSV000085434 | MassIVE
Project description:Autoimmune neuroinflammation occurs when an individual’s immune cells attack the brain, spinal cord or peripheral nerves. Several Suppressor of Cytokine Signaling (SOCS) proteins have been shown to limit pro-inflammatory signaling pathways in myeloid cells and prevent neuroinflammation. They rely on several mechanisms to accomplish this. Their SH2 domain allows them to bind phosphorylated tyrosine residues on surface receptors to prevent downstream signaling while their C-terminal SOCS domain can promote their assembly with Cullin5 (CUL5) to degrade signaling proteins. To date, the role of CUL5 in myeloid-cell-mediated function is poorly understood. Here we show that loss of Cul5 in myeloid cells resulted in reduced neuroinflammation and attenuated progression of Experimental Autoimmune Encephalomyelitis (EAE). Although peripheral CD4+ T cell activation was not overtly affected, Cul5-deficient macrophages in the Central Nervous System (CNS) demonstrated a significant shift towards an anti-inflammatory phenotype, characterized by increased expression of Arginase 1. This correlated with an enhanced frequency of FoxP3+ regulatory T cells. In contrast to what would be predicted if CUL5 and SOCS proteins work together to degrade pro-inflammatory cytokine signaling, Cul5 deletion in myeloid cells selectively enhanced IL-4-mediated Arginase 1 expression. These findings identify CUL5 as an unanticipated pro-inflammatory mediator during neuroinflammation and reveal its potential as a therapeutic target for autoimmune diseases.
2025-08-04 | PXD066533 | Pride
Project description:Genes and pathways in which inactivation dampens tissue inflammation present new opportunities for understanding the pathogenesis of common human inflammatory diseases, including inflammatory bowel disease, rheumatoid arthritis and multiple sclerosis. We identified a mutation in the gene encoding the deubiquitination enzyme USP15 (Usp15L749R) that protected mice against both experimental cerebral malaria (ECM) induced by Plasmodium berghei and experimental autoimmune encephalomyelitis (EAE). Combining immunophenotyping and RNA sequencing in brain (ECM) and spinal cord (EAE) revealed that Usp15L749R-associated resistance to neuroinflammation was linked to dampened type I interferon responses in situ. In hematopoietic cells and in resident brain cells, USP15 was coexpressed with, and functionally acted together with the E3 ubiquitin ligase TRIM25 to positively regulate type I interferon responses and to promote pathogenesis during neuroinflammation. The USP15-TRIM25 dyad might be a potential target for intervention in acute or chronic states of neuroinflammation.
2016-10-10 | GSE79702 | GEO
Project description:A20 is a ubiquitin-modifying protein that negatively regulates canonical NF-κB signaling and mutations in A20/TNFAIP3 have been associated with a variety of autoimmune diseases, including multiple sclerosis (MS). We found that deletion of A20 in central nervous system (CNS) endothelial cells (BEC) enhances experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. These mice showed increased numbers of CNS-infiltrating immune cells during neuroinflammation and in the steady state. While the integrity of the barrier was not impaired, we observed a strong activation of the endothelium in A20ΔBEC mice, with dramatically increased levels of the adhesion molecules ICAM-1 and VCAM-1. We furthermore discovered ICOSL as novel adhesion molecule expressed by A20-deficient BECs. Silencing of ICOSL in BECs ameliorated the severity of an active EAE disease in wildtype mice and significantly delayed the onset of symptom development. Furthermore, blocking of ICOSL on primary CNS-derived endothelial cells impaired the adhesion of different T cell populations to the monolayer. Taken together, we here report a novel function of A20-regulated ICOSL expressed on CNS endothelial cells during inflammation. We propose that BEC-ICOSL contributes to the firm adhesion of T cells to the barrier, promoting T cell transmigration into the CNS and eventually driving autoimmune neuroinflammation.
2023-11-03 | GSE221318 | GEO
Project description:Microglial activation during neuroinflammation is crucial for coordinating the immune response against neuronal tissue and the initial response of microglia determines the severity of neuroinflammatory diseases. CD83 has been associated with early activation of microglia in various disease settings albeit its functional relevance for microglial biology was still elusive. Thus, we conducted a thorough assessment of CD83 regulation in microglia as well as its impact on microglial mediated neuroinflammation. Here, we describe for the first time that CD83 expression in microglia is not only associated with cellular activation but also with pro-resolving functions. Conditional deletion of CD83 causes malfunctioning responses to myelin debris, which results in an over-activated state during autoimmune neuroinflammation. Subsequently, CD83-deficient microglia recruit more pathogenic immune cells to the central nervous system and deteriorate resolving mechanism, which exacerbates the disease. Thus, CD83 in microglia orchestrates cellular activation and consequently, also resolution of neuroinflammation.
2023-06-28 | GSE230753 | GEO