Type I interferon limits central nervous system autoimmunity by modulating the microRNA-21-FOXO1 axis in pathogenic T helper 17 cells.

Abstract

IFN-β, a type I interferon, has been used as a first-line therapy for patients with multiple sclerosis (MS) for more than 30 years; however, the cellular and molecular basis of its therapeutic efficacy remains unclear. Here, we first used experimental autoimmune encephalomyelitis (EAE), a mouse model for MS, to show that the therapeutic effects of IFN-β were associated with a down-regulation of microRNA-21 (miR-21) and pathogenic T_H17 (pT_H17) cells. In vitro experiments demonstrated that genetic knockout of miR-21 directly inhibited pathogenic T_H17 cell differentiation. Further mechanistic investigations revealed that miR-21 promoted pathogenic T_H17 differentiation by inhibiting the transcription factor <i>Forkhead box protein O1</i> (<i>Foxo1</i>). Accordingly, miR-21 loss abrogated pathogenic T_H17 differentiation and conferred resistance to EAE. Treatment of T cell monocultures with IFN-β showed that IFN-β did not directly limit miR-21 expression. Instead, IFN-β treatment inhibited the secretion of miR-21-inducing cytokines from myeloid cells, reduced miR-21 induction within cocultured T cells, and inhibited pathogenic T_H17 development. In patient samples, immunophenotypic and targeted transcriptomic analyses revealed that compared with IFN-β treatment responders, nonresponders expressed elevated miR-21-inducing cytokines within myeloid cells, alongside increased miR-21 and pathogenic T_H17 cytokines within CD4⁺ T cells. Direct miR-21 inhibition reduced pathogenic T_H17 differentiation in nonresponder CD4⁺ T cells. These results suggest that type I IFN signaling limits central nervous system autoimmunity by inhibiting miR-21-mediated pathogenic T_H17 development. miR-21 inhibition may be of potential therapeutic value specifically for the IFN-β nonresponder cohort.