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MicroRNA-150 controls experimental autoimmune encephalomyelitis by regulating CD4 T cell differentiation and function [RNA-seq II]

ABSTRACT: MicroRNAs are small non-coding RNA molecules that fine-tune diverse biological processes and are often found to be dysregulated in diseases, such as multiple sclerosis (MS). MS is an immune-mediated disease of the central nervous system characterized by demyelination, axonal loss and neurodegeneration. We have previously shown microRNA-150 (miR-150) levels to be elevated in cell-free cerebrospinal fluid (CSF) of MS patients compared to controls. We aimed to investigate the physiopathological function of miR-150 in vivo by generating miR-150 knock-out (KO) and knock-in (KI) mice using CRISPR/Cas9 technology. To specifically interrogate the role of miR-150 upon inflammation of the central nervous system (CNS), we induced experimental autoimmune encephalomyelitis (EAE), a mouse model for MS, in these newly generated mice. After induction of EAE, miR-150KO mice developed milder disease compared to WT littermate controls while miR-150KI mice presented with exacerbated EAE. Disease amelioration in miR-150KO was accompanied by decreased infiltration of CD4+ T cells in the central nervous system compared to WT and KI mice, as well as increased FoxP3+ regulatory T (Treg) cells in inguinal lymph nodes at disease priming stage. We demonstrated that Treg cells were fundamental for EAE amelioration in miR-150KO mice, as their partial depletion during EAE priming stage in miR-150KO FoxP3DTR mice restored disease incidence and severity to the levels observed in WT and KI mice. Transcriptomic profiling of CD4+ T cells isolated from miR-150KO mice revealed upregulation of genes associated with Treg cell function, but also reduced gene translation and autophagy, as compared to WT and particularly KI cells. The role of miR-150 in affecting the fate of CD4+ T cells was further supported by the grater tendency of miR-150KO CD4+ T cells to differentiate into Treg cells in-vitro. In conclusion, miR-150 deficiency favored considerably milder CNS inflammation by promoting differentiation of a more anti-inflammatory CD4+ T cell repertoire.

ORGANISM(S): Mus musculus

PROVIDER: GSE227844 | GEO | 2025/01/01

REPOSITORIES: GEO

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Project description:Vitamin D3 (VitD) insufficiency is postulated to represent a major modifiable risk factor for multiple sclerosis (MS). While low VitD levels strongly correlate with higher MS risk in white populations, this is not the case for other ethnic groups, suggesting the existence of a genetic component. Moreover, VitD supplementation studies in MS so far have not shown a consistent benefit. We sought to determine whether direct manipulation of VitD levels modulates central nervous system (CNS) autoimmune disease in a sex-by-genotype-dependent manner. To this end, we used a dietary model of VitD modulation, together with the autoimmune animal model of MS, experimental autoimmune encephalomyelitis (EAE). To assess the impact of genotype-by-VitD interactions on EAE susceptibility, we utilized a chromosome substitution (consomic) mouse model that incorporates the genetic diversity of wild-derived PWD/PhJ mice. High VitD was protective in EAE in female, but not male C57BL/6J (B6) mice, and had no effect in EAE-resistant PWD/PhJ (PWD) mice. EAE protection was accompanied by sex- and genotype-specific suppression of proinflammatory transcriptional programs in effector CD4 T effector cells, but not CD4 Treg cells. Decreased expression of proinflammatory genes was observed with high VitD in female CD4 T cells, specifically implicating a key role of MHC class II genes, interferon gamma, and Th1 cell-mediated neuroinflammation. In consomic strains, effects of VitD on EAE were also sex- and genotype-dependent, whereby high VitD: 1) was protective, 2) had no effect, and, 3) unexpectedly had disease-exacerbating effects. Systemic levels of 25(OH)D differed across consomic strains, with higher levels associated with EAE protection only in females. Analysis of expression of key known VitD metabolism genes between B6 and PWD mice revealed that their expression is genetically determined and sex-specific, and implicated Cyp27b1 and Vdr as candidate genes responsible for differential EAE responses to VitD modulation. Taken together, our results support the observation that the association between VitD status and MS susceptibility is genotype-dependent, and suggest that the outcome of VitD status in MS is determined by gene-by-sex interactions.

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MicroRNA-150 controls experimental autoimmune encephalomyelitis by regulating CD4 T cell differentiation and function [RNA-seq II]

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