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
{"title":"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","authors":"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","doi":"10.1126/scitranslmed.adp5802","DOIUrl":null,"url":null,"abstract":"<div >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<sub>H</sub>17 (pT<sub>H</sub>17) cells. In vitro experiments demonstrated that genetic knockout of miR-21 directly inhibited pathogenic T<sub>H</sub>17 cell differentiation. Further mechanistic investigations revealed that miR-21 promoted pathogenic T<sub>H</sub>17 differentiation by inhibiting the transcription factor <i>Forkhead box protein O1</i> (<i>Foxo1</i>). Accordingly, miR-21 loss abrogated pathogenic T<sub>H</sub>17 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<sub>H</sub>17 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<sub>H</sub>17 cytokines within CD4<sup>+</sup> T cells. Direct miR-21 inhibition reduced pathogenic T<sub>H</sub>17 differentiation in nonresponder CD4<sup>+</sup> T cells. These results suggest that type I IFN signaling limits central nervous system autoimmunity by inhibiting miR-21–mediated pathogenic T<sub>H</sub>17 development. miR-21 inhibition may be of potential therapeutic value specifically for the IFN-β nonresponder cohort.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 815","pages":""},"PeriodicalIF":14.6000,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adp5802","citationCount":"0","resultStr":"{\"title\":\"Type I interferon limits central nervous system autoimmunity by modulating the microRNA-21–FOXO1 axis in pathogenic T helper 17 cells\",\"authors\":\"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\",\"doi\":\"10.1126/scitranslmed.adp5802\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div >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<sub>H</sub>17 (pT<sub>H</sub>17) cells. In vitro experiments demonstrated that genetic knockout of miR-21 directly inhibited pathogenic T<sub>H</sub>17 cell differentiation. Further mechanistic investigations revealed that miR-21 promoted pathogenic T<sub>H</sub>17 differentiation by inhibiting the transcription factor <i>Forkhead box protein O1</i> (<i>Foxo1</i>). Accordingly, miR-21 loss abrogated pathogenic T<sub>H</sub>17 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<sub>H</sub>17 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<sub>H</sub>17 cytokines within CD4<sup>+</sup> T cells. 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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.
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.
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