microRNA-92a promotes CNS autoimmunity by modulating the regulatory and inflammatory T cell balance
Mai Fujiwara, … , Howard L. Weiner, Gopal Murugaiyan
Mai Fujiwara, … , Howard L. Weiner, Gopal Murugaiyan
Published March 17, 2022
Citation Information: J Clin Invest. 2022;132(10):e155693. https://doi.org/10.1172/JCI155693.
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Research Article Autoimmunity Inflammation

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

Abstract

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.

Authors

Mai Fujiwara, Radhika Raheja, Lucien P. Garo, Amrendra K. Ajay, Ryoko Kadowaki-Saga, Sukrut H. Karandikar, Galina Gabriely, Rajesh Krishnan, Vanessa Beynon, Anu Paul, Amee Patel, Shrishti Saxena, Dan Hu, Brian C. Healy, Tanuja Chitnis, Roopali Gandhi, Howard L. Weiner, Gopal Murugaiyan

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Figure 5

miR-92a promotes nonpathogenic and pathogenic Th17 development by targeting Foxo1.

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miR-92a promotes nonpathogenic and pathogenic Th17 development by target...
(A) qPCR analysis of Foxo1 expression in nonpathogenic Th17-polarized WT and Mir92a–/– naive CD4+ T cells (n = 3–4). (B) ChIP analysis of RORγt binding to the Il17a locus in nonpathogenic Th17-polarized WT and Mir92a–/– naive CD4+ T cells (n = 3–4). (C) Representative flow cytometric plots and frequencies of IL-17A–GFP+ cells in Il17agfp and Mir92a–/– Il17agfp naive CD4+ T cells, transfected in vitro with control or Foxo1 siRNA and then cultured under nonpathogenic Th17-polarizing conditions (n = 3). (D) qPCR analysis of Foxo1 expression in pathogenic Th17-polarized WT and Mir92a–/– naive CD4+ T cells (n = 4). (E and F) ChIP analyses of RORγt binding to the Il1r1 promoter loci (E) and Il23r promoter loci (F) in pathogenic Th17-polarized WT and Mir92a–/– naive CD4+ T cells (n = 3–4). (G and H) Representative flow cytometric histograms and MFIs of IL-1R (G) and IL-23R (H) in pathogenic Th17-polarized WT and Mir92a–/– CD4+ T cells (n = 4). MFI values shown were obtained after subtracting the MFI values of fluorescence minus one (FMO) controls for IL-1R or IL-23R. (I) Representative flow cytometric plots and frequencies of IL-17A+GM-CSF+ cells from G and H (n = 4). (J) Representative flow cytometric plots and frequencies of IL-17A+GM-CSF+ cells in WT and Mir92a–/– naive CD4+ T cells transfected with control or Foxo1 siRNA followed by culturing under pathogenic Th17-polarizing conditions (n = 3). Fold enrichment is shown relative to WT IgG conditions (B, G, and H). Data are representative of 2 independent experiments and indicate the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001, by unpaired, 2-tailed Student’s t test (A, D, G–I) or 1-way ANOVA with Dunnet’s multiple-comparison test (B, C, E, F, and J).