I型干扰素通过调节致病性T辅助17细胞中的microRNA-21-FOXO1轴来限制中枢神经系统自身免疫

IF 14.6 1区 医学 Q1 CELL BIOLOGY
Johnna Francis Varghese, Mai Fujiwara, Amrendra K. Ajay, Lucien P. Garo, Alkeiver Cannon, Ryoko Kadowaki-Saga, Galina Gabriely, Fernando Pradella, Breno Ferrari, Rohit Patel, Shivnarayan Dhuppar, Rachael Rossi Cecere, Panagiota Kolypetri, Rajesh Krishnan, Shrishti Saxena, Brian Healy, Gauruv Bose, Howard L. Weiner, Tanuja Chitnis, Gopal Murugaiyan
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引用次数: 0

摘要

IFN-β是一种I型干扰素,已被用作多发性硬化症(MS)患者的一线治疗超过30年;然而,其治疗效果的细胞和分子基础尚不清楚。在这里,我们首先使用实验性自身免疫性脑脊髓炎(EAE), MS的小鼠模型,来证明IFN-β的治疗作用与microRNA-21 (miR-21)和致病性TH17 (pTH17)细胞的下调有关。体外实验表明,基因敲除miR-21可直接抑制致病性TH17细胞的分化。进一步的机制研究表明,miR-21通过抑制转录因子叉头盒蛋白O1 (Foxo1)促进致病性TH17分化。因此,miR-21缺失消除了致病性TH17分化并赋予了对EAE的抗性。用IFN-β处理T细胞单培养表明IFN-β没有直接限制miR-21的表达。相反,IFN-β处理抑制髓细胞分泌miR-21诱导细胞因子,减少共培养T细胞内miR-21的诱导,并抑制致病性TH17的发展。在患者样本中,免疫表型和靶向转录组分析显示,与IFN-β治疗应答者相比,无应答者在髓细胞中表达升高的miR-21诱导细胞因子,同时在CD4+ T细胞中表达升高的miR-21和致病性TH17细胞因子。直接抑制miR-21可降低无应答CD4+ T细胞中致病性TH17分化。这些结果表明I型IFN信号通过抑制mir -21介导的致病性TH17的发展来限制中枢神经系统自身免疫。miR-21抑制可能具有潜在的治疗价值,特别是对于IFN-β无反应队列。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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

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.
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来源期刊
Science Translational Medicine
Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL
CiteScore
26.70
自引率
1.20%
发文量
309
审稿时长
1.7 months
期刊介绍: Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research. The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases. The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine. The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.
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