# Type I Interferon Signaling Augments Autoimmunity in Neuromyelitis Optica Spectrum Disorder

## TL;DR

This study shows that the cGAS-STING-IFN-I pathway worsens NMOSD by boosting harmful immune responses, suggesting that blocking this pathway could be a new treatment.

## Contribution

The study identifies the cGAS-STING-IFN-I pathway as a driver of autoimmunity in NMOSD and proposes it as a therapeutic target.

## Key findings

- The cGAS-STING-IFN-I pathway is overactive in myeloid cells in NMOSD patients.
- Blocking the STING pathway reduces AQP4-specific T cell activation and astrocyte damage in mouse models.
- STING inhibitor H151 treatment alleviates NMOSD severity in animal models.

## 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.

The cGAS‐STING innate immune pathway is excessively activated both in peripheral monocytes and CNS microglia in patients with NMOSD, leading to an overproduction of IFN‐I. IFN‐I subsequently acts on AQP4‐specific autoreactive T cells. Blocking this pathway may offer novel therapeutic options for individuals with NMOSD.