microRNA-92a promotes CNS autoimmunity by modulating the regulatory and inflammatory T cell balance
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
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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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 6

miR-92a inhibitor treatment ameliorates EAE.

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miR-92a inhibitor treatment ameliorates EAE. (A) qPCR analysis of miR-92...
(A) qPCR analysis of miR-92a in splenic CD4+ T cells cultured in vitro with miR-92a or a control inhibitor (n = 5). (B–D) Representative flow cytometric plots and frequencies of IFN-γ+ (n = 5) (B), Foxp3+ (n = 7) (C), and IL-17A+ (n = 8) (D) cells among WT naive CD4+ T cells cultured under either Th1- (B), Treg- (C), or (D) nonpathogenic Th17-polarizing conditions with miR-92a or a control inhibitor, respectively. (E and F) Representative flow cytometric histograms and MFIs of IL-1R (E) and IL-23R (F) in pathogenic Th17-polarized WT naive CD4+ T cells cultured with a control or miR-92a inhibitor (n = 4). MFI values shown were obtained after subtracting the MFI values of the FMO controls for IL-1R or IL-23R. (G) Representative flow cytometric plots and frequencies of IL-17A+GM-CSF+ cells under the same conditions as in E and F. (H and I) qPCR analyses of miR-92a levels in total splenocytes (H) and splenic CD4+ T cells (I) from control and miR-92a inhibitor–treated mice (n = 3). (J) Clinical EAE scores for treated WT mice (n = 5–7). (K and L) Representative flow cytometric plots and frequencies of IFN-γ+, IL-17A+, GM-CSF+ (K), and Foxp3+ (L), splenic CD4+ T cells from treated mice at EAE onset (n = 6). Data are representative of 2 or more independent experiments and indicate the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001, by paired, 2-tailed Student’s t test (A–G), unpaired, 2-tailed Student’s t test (H, I, and L), Mann-Whitney U test (J), or 1-way ANOVA with Šidák’s multiple-comparison test between control inhibitor and miR-92a inhibitor treatment within each condition (K).