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
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Renal Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Sci Transl Med. 2025 Sep 10;17(815):eadp5802. doi: 10.1126/scitranslmed.adp5802.
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 T17 (pT17) cells. In vitro experiments demonstrated that genetic knockout of miR-21 directly inhibited pathogenic T17 cell differentiation. Further mechanistic investigations revealed that miR-21 promoted pathogenic T17 differentiation by inhibiting the transcription factor (). Accordingly, miR-21 loss abrogated pathogenic T17 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 T17 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 T17 cytokines within CD4 T cells. Direct miR-21 inhibition reduced pathogenic T17 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 T17 development. miR-21 inhibition may be of potential therapeutic value specifically for the IFN-β nonresponder cohort.
I型干扰素IFN-β已被用作治疗多发性硬化症（MS）患者的一线疗法30多年；然而，其治疗效果的细胞和分子基础仍不清楚。在此，我们首先使用实验性自身免疫性脑脊髓炎（EAE，一种MS的小鼠模型）来表明IFN-β的治疗效果与微小RNA-21（miR-21）和致病性T17（pT17）细胞的下调有关。体外实验表明，miR-21的基因敲除直接抑制了致病性T17细胞的分化。进一步的机制研究表明，miR-21通过抑制转录因子（）促进致病性T17分化。因此，miR-21的缺失消除了致病性T17分化并赋予对EAE的抗性。用IFN-β处理T细胞单培养物表明，IFN-β并不直接限制miR-21的表达。相反，IFN-β处理抑制了髓样细胞中诱导miR-21的细胞因子的分泌，减少了共培养T细胞内miR-21的诱导，并抑制了致病性T17的发育。在患者样本中，免疫表型和靶向转录组分析显示，与IFN-β治疗反应者相比，无反应者在髓样细胞中表达升高的诱导miR-21的细胞因子，同时CD4 T细胞内的miR-21和致病性T17细胞因子增加。直接抑制miR-21可减少无反应者CD4 T细胞中致病性T17的分化。这些结果表明，I型干扰素信号通过抑制miR-21介导的致病性T17发育来限制中枢神经系统自身免疫。抑制miR-21可能对IFN-β无反应者队列具有潜在的治疗价值。
