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journal article·2025-10Open access

Type I Interferon Signaling Augments Autoimmunity in Neuromyelitis Optica Spectrum Disorder

Tian‐Xiang Zhang, Xiaoxiao Yang, Xue Gao, Xiaoshan Du, Xuegan Lian, Naiyuan Shao, Ye Liu, Zhenning Huang, Dongmei Jia, Alexander Y. L. Lau, Zhiguo Li, Zaal Kokaia, Fu‐Dong Shi, Chao Zhang

Advanced Science· Volume 12· Issue 38
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Source abstract

Abstract

Abstract Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease characterized by anti‐aquaporin 4 (AQP4) antibody‐mediated astrocyte damage and subsequent demyelination. Prior attempts to treat NMOSD with interferon‐beta (IFN‐β), a disease‐modifying therapy for multiple sclerosis, resulted in worsening of disease activity, with an unknown mechanism. Here, robust activation of the cGAS‐STING‐IFN‐I signaling pathway is identified in myeloid cells in both the periphery and central nervous system. The abnormal IFN‐I response gives rise to an increase in the number of AQP4 antigen‐specific autoreactive T cells. Sting deficiency can significantly blunt the activation of AQP4‐specific T cells, as well as the IFN‐I activity in microglia, and attenuate astrocyte damage. Consequently, the clinical manifestation of NMOSD is ameliorated in a passive transfer mouse model of NMOSD. Further, treatment with STING inhibitor H151 alleviates the severity of NMOSD mouse models. These findings uncover the cGAS‐STING‐IFN‐I pathway in promoting autoreactive T cells and establish a foundation for inhibiting this pathway as a new therapeutic revenue for NMOSD.
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Research context

OpenAlex topics: Multiple Sclerosis Research Studies · interferon and immune responses · Systemic Lupus Erythematosus Research

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Neurology Tianjin Medical University General Hospital Tianjin 300052 China

Department of Bioinformatics School of Basic Medical Sciences Tianjin Medical University Tianjin 300070 China

Department of Neurology The Third Affiliated Hospital of Soochow University Changzhou Jiangsu 213003 China

Department of Neurosurgery The Third Affiliated Hospital of Soochow University Changzhou Jiangsu 213003 China

Division of Neurology Department of Medicine and Therapeutics, Faculty of Medicine The Chinese University of Hong Kong Shatin Hong Kong 999077 China

Laboratory of Stem Cells and Restorative Neurology Lund Stem Cell Center Lund University Lund 22184 Sweden

Department of Neurology China National Clinical Research Center for Neurological Diseases Beijing Tiantan Hospital Capital Medical University Beijing 100070 China

State Key Laboratory of Experimental Hematology National Clinical Research Center for Blood Diseases Haihe Laboratory of Cell Ecosystem Tianjin 300052 China

Funding

National Natural Science Foundation of China · Peking Union Medical College · Natural Science Foundation of Tianjin Municipal Science and Technology Commission

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