Type I Interferon Signaling Augments Autoimmunity in Neuromyelitis Optica Spectrum Disorder
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.
Authors
- Alexander Yuk Lun Lau (ORCID: https://orcid.org/0000-0002-5933-9290)
- Xue Gao
- Z. Josh Huang (ORCID: https://orcid.org/0000-0003-0592-028X)
- Zaal Kokaia (ORCID: https://orcid.org/0000-0003-2296-2449)
- Xiaoxiao Yang (ORCID: https://orcid.org/0000-0001-9895-9559)
- Nan Shao (ORCID: https://orcid.org/0000-0001-5523-7142)
- Xiaoshan Du
- Ye Liu (ORCID: https://orcid.org/0000-0001-5581-9046)
- Zhiguo Li (ORCID: https://orcid.org/0000-0002-6869-2766)
- Chao Zhang (ORCID: https://orcid.org/0000-0002-0659-4597)
- Fu‐Dong Shi (ORCID: https://orcid.org/0000-0002-9675-4637)
- Tianxiang Zhang (ORCID: https://orcid.org/0000-0001-9957-9478)
- Xuegan Lian (ORCID: https://orcid.org/0009-0003-9319-1095)
- Dongmei Jia
Institutions
- Chinese University of Hong Kong (HK)
- Capital Medical University (CN)
- Lund University (SE)
- Tianjin Medical University General Hospital (CN)
- Soochow University (CN)
- Beijing Tian Tan Hospital (CN)
- National Clinical Research Center for Digestive Diseases (CN)
- Institute of Hematology & Blood Diseases Hospital (CN)
- Changzhou Third People's Hospital (CN)
- Tianjin Medical University (CN)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-07-21
- DOI
- https://doi.org/10.1002/advs.202500942
- Primary Topic
- Multiple Sclerosis Research Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Science Foundation
- National Natural Science Foundation of China
- Peking Union Medical College
- Bijzonder Onderzoeksfonds UGent
- Natural Science Foundation of Tianjin Municipal Science and Technology Commission