2. Academic Validation
  3. Type I Interferon Signaling Augments Autoimmunity in Neuromyelitis Optica Spectrum Disorder

Type I Interferon Signaling Augments Autoimmunity in Neuromyelitis Optica Spectrum Disorder

  • Adv Sci (Weinh). 2025 Jul 21:e00942. doi: 10.1002/advs.202500942.
Tian-Xiang Zhang 1,  Xiaoxiao Yang 2,  Xue Gao 1,  Xiaoshan Du 1,  Xuegan Lian 3,  Naiyuan Shao 4,  Ye Liu 1,  Zhenning Huang 1,  Dongmei Jia 1,  Alexander Y L Lau 5,  Zhiguo Li 1,  Zaal Kokaia 6,  Fu-Dong Shi 1 7,  Chao Zhang 1 3 7 8
Affiliations

Affiliations

  • 1 Department of Neurology, Tianjin Medical University General Hospital, Tianjin, 300052, China.
  • 2 Department of Bioinformatics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.
  • 3 Department of Neurology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, 213003, China.
  • 4 Department of Neurosurgery, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, 213003, China.
  • 5 Division of Neurology, Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, 999077, China.
  • 6 Laboratory of Stem Cells and Restorative Neurology, Lund Stem Cell Center, Lund University, Lund, 22184, Sweden.
  • 7 Department of Neurology, China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China.
  • 8 State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Tianjin, 300052, China.
PMID: 40686188 DOI: 10.1002/advs.202500942
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.

Keywords

T cells; innate immune response; neuromyelitis optica spectrum disorder; type I interferon.

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