W204 - MiRNA-21 Control of Type I Interferon Signaling in CNS Autoimmunity

Abstract Text: IFN-beta, a type I interferon, has been used as a first-line therapy for patients with multiple sclerosis (MS) for thirty years; however, the cellular and molecular basis of its therapeutic efficacy remains largely unknown. Here, we report that IFN-beta and type I IFN signaling limits central nervous system autoimmunity by inhibiting microRNA-21 (miR-21)-mediated pathogenic Th17 development. Briefly, IFN-beta limits miR-21 expression within CD4+ T cells, including miR-21-mediated pathogenic Th17 development, by downregulating miR-21-inducing cytokines within myeloid cells. We show miR-21 itself promotes pathogenic Th17 differentiation by inhibiting a key transcription factor, Foxo1. Accordingly, miR-21 loss abrogates pathogenic Th17 differentiation and confers resistance to experimental autoimmune encephalomyelitis, a mouse model of MS. In patient samples, we found that compared to responders of IFN-beta treatment, non-responders express elevated miR-21-inducing cytokines within myeloid cells, alongside increased miR-21 and pathogenic Th17 cytokines within CD4+ T cells. Finally, direct miR-21 inhibition reduces pathogenic Th17 differentiation in non-responder CD4+ T cells. These findings provide insights into the mechanisms underlying IFN-beta therapy in MS patients, suggesting that miR-21 may be a potential biomarker to predict therapeutic response, and raises the possibility that miR-21 inhibition may be of potential therapeutic value specifically for the IFN-beta non-responder cohort.