H-151

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.

JOURNAL/nrgr/04.03/01300535-202508000-00026/figure1/v/2024-09-30T120553Z/r/image-tiff Interferon regulatory factor 7 plays a crucial role in the innate immune response. However, whether interferon regulatory factor 7-mediated signaling contributes to Parkinson’s disease remains unknown. Here we report that interferon regulatory factor 7 is markedly up-regulated in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine–induced mouse model of Parkinson’s disease and co-localizes with microglial cells. Both the selective cyclic guanosine monophosphate adenosine monophosphate synthase inhibitor RU.521 and the stimulator of interferon genes inhibitor H151 effectively suppressed interferon regulatory factor 7 activation in BV2 microglia exposed to 1-methyl-4-phenylpyridinium and inhibited transformation of mouse BV2 microglia into the neurotoxic M1 phenotype. In addition, siRNA-mediated knockdown of interferon regulatory factor 7 expression in BV2 microglia reduced the expression of inducible nitric oxide synthase, tumor necrosis factor α, CD16, CD32, and CD86 and increased the expression of the anti-inflammatory markers ARG1 and YM1. Taken together, our findings indicate that the cyclic guanosine monophosphate adenosine monophosphate synthase–stimulator of interferon genes–interferon regulatory factor 7 pathway plays a crucial role in the pathogenesis of Parkinson’s disease