microRNA-92a promotes CNS autoimmunity by modulating the regulatory and inflammatory T cell balance

A disequilibrium between immunosuppressive Tregs and inflammatory IL-17-producing Th17 cells is a hallmark of autoimmune diseases, including multiple sclerosis (MS). However, the molecular mechanisms underlying the Treg and Th17 imbalance in CNS autoimmunity remain largely unclear. Identifying the f...

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Vydané v:	The Journal of clinical investigation Ročník 132; číslo 10; s. 1 - 16
Hlavní autori:	Fujiwara, Mai, Raheja, Radhika, Garo, Lucien P., Ajay, Amrendra K., Kadowaki-Saga, Ryoko, Karandikar, Sukrut H., Gabriely, Galina, Krishnan, Rajesh, Beynon, Vanessa, Paul, Anu, Patel, Amee, Saxena, Shrishti, Hu, Dan, Healy, Brian C., Chitnis, Tanuja, Gandhi, Roopali, Weiner, Howard L., Murugaiyan, Gopal
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States American Society for Clinical Investigation 16.05.2022
Predmet:	Animals Autoimmune diseases Autoimmunity Biomedical research CD4 antigen Cell Differentiation Cellular control mechanisms Cytokines Development and progression Disease Encephalomyelitis Encephalomyelitis, Autoimmune, Experimental - genetics Encephalomyelitis, Autoimmune, Experimental - immunology Experimental allergic encephalomyelitis FOXO1 protein Gene expression Genetic aspects Health aspects Helper cells Humans Inflammation Interleukin 17 Lymphocytes Lymphocytes T Mice Mice, Inbred C57BL MicroRNA MicroRNAs MicroRNAs - genetics miRNA Molecular modelling Multiple sclerosis Multiple Sclerosis - genetics Multiple Sclerosis - immunology Pathogenesis Patients T cells T-Lymphocytes, Regulatory Th1 Cells Th17 Cells Therapeutic targets Transcription factors United States Autoimmunity Multiple sclerosis Inflammation Autoimmune diseases T cells
ISSN:	1558-8238, 0021-9738, 1558-8238
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Shrnutí:	A disequilibrium between immunosuppressive Tregs and inflammatory IL-17-producing Th17 cells is a hallmark of autoimmune diseases, including multiple sclerosis (MS). However, the molecular mechanisms underlying the Treg and Th17 imbalance in CNS autoimmunity remain largely unclear. Identifying the factors that drive this imbalance is of high clinical interest. Here, we report a major disease-promoting role for microRNA-92a (miR-92a) in CNS autoimmunity. miR-92a was elevated in experimental autoimmune encephalomyelitis (EAE), and its loss attenuated EAE. Mechanistically, miR-92a mediated EAE susceptibility in a T cell-intrinsic manner by restricting Treg induction and suppressive capacity, while supporting Th17 responses, by directly repressing the transcription factor Foxo1. Although miR-92a did not directly alter Th1 differentiation, it appeared to indirectly promote Th1 cells by inhibiting Treg responses. Correspondingly, miR-92a inhibitor therapy ameliorated EAE by concomitantly boosting Treg responses and dampening inflammatory T cell responses. Analogous to our findings in mice, miR-92a was elevated in CD4+ T cells from patients with MS, and miR-92a silencing in patients' T cells promoted Treg development but limited Th17 differentiation. Together, our results demonstrate that miR-92a drives CNS autoimmunity by sustaining the Treg/Th17 imbalance and implicate miR-92a as a potential therapeutic target for MS.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Authorship note: MF and RR contributed equally to this work.
ISSN:	1558-8238 0021-9738 1558-8238
DOI:	10.1172/JCI155693