Type I Interferon Signaling Augments Autoimmunity in Neuromyelitis Optica Spectrum Disorder

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.