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Type I Interferon Signaling Augments Autoimmunity in Neuromyelitis Optica Spectrum Disorder

Zhang, Tian Xiang ; Yang, Xiaoxiao ; Gao, Xue ; Du, Xiaoshan ; Lian, Xuegan ; Shao, Naiyuan ; Liu, Ye ; Huang, Zhenning ; Jia, Dongmei and Lau, Alexander Y.L. , et al. (2025) In Advanced Science 12(38).
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... (More)

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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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
innate immune response, neuromyelitis optica spectrum disorder, T cells, type I interferon
in
Advanced Science
volume
12
issue
38
article number
e00942
publisher
John Wiley & Sons Inc.
external identifiers
  • scopus:105011295331
  • pmid:40686188
ISSN
2198-3844
DOI
10.1002/advs.202500942
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2025 The Author(s). Advanced Science published by Wiley-VCH GmbH.
id
03a0339b-0826-434e-adf7-9ac4ae3d052b
date added to LUP
2026-01-26 13:37:47
date last changed
2026-01-26 15:29:46
@article{03a0339b-0826-434e-adf7-9ac4ae3d052b,
  abstract     = {{<p>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.</p>}},
  author       = {{Zhang, Tian Xiang and Yang, Xiaoxiao and Gao, Xue and Du, Xiaoshan and Lian, Xuegan and Shao, Naiyuan and Liu, Ye and Huang, Zhenning and Jia, Dongmei and Lau, Alexander Y.L. and Li, Zhiguo and Kokaia, Zaal and Shi, Fu Dong and Zhang, Chao}},
  issn         = {{2198-3844}},
  keywords     = {{innate immune response; neuromyelitis optica spectrum disorder; T cells; type I interferon}},
  language     = {{eng}},
  month        = {{10}},
  number       = {{38}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Advanced Science}},
  title        = {{Type I Interferon Signaling Augments Autoimmunity in Neuromyelitis Optica Spectrum Disorder}},
  url          = {{http://dx.doi.org/10.1002/advs.202500942}},
  doi          = {{10.1002/advs.202500942}},
  volume       = {{12}},
  year         = {{2025}},
}