Интерферон типа I ограничивает автонепроницаемость центральной нервной системы путем модуляции оси микроRNA-21-FOXO1 в патогенном Т-помощнике 17 клеток.
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Varghese Johnna Francis, Fujiwara Mai, Ajay Amrendra K, Garo Lucien P, Cannon Alkeiver, Kadowaki-Saga Ryoko, Gabriely Galina, Pradella Fernando, Ferrari Breno, Patel Rohit, Dhuppar Shivnarayan, Cecere Rachael Rossi, Kolypetri Panagiota, Krishnan Rajesh, Saxena Shrishti, Healy Brian, Bose Gauruv, Weiner Howard L, Chitnis Tanuja, Murugaiyan Gopal
Аннотация
Оригинал публикации
Type I interferon limits central nervous system autoimmunity by modulating the microRNA-21-FOXO1 axis in pathogenic T helper 17 cells.
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 TH17 (pTH17) cells. In vitro experiments demonstrated that genetic knockout of miR-21 directly inhibited pathogenic TH17 cell differentiation. Further mechanistic investigations revealed that miR-21 promoted pathogenic TH17 differentiation by inhibiting the transcription factor Forkhead box protein O1 (Foxo1). Accordingly, miR-21 loss abrogated pathogenic TH17 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 TH17 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 TH17 cytokines within CD4+ T cells. Direct miR-21 inhibition reduced pathogenic TH17 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 TH17 development. miR-21 inhibition may be of potential therapeutic value specifically for the IFN-β nonresponder cohort.