The <scp>IL</scp> ‐1β‐ <scp>STING</scp> Signaling Axis Drives Neuromyelitis Optica Pathogenesis in a Murine Model

OBJECTIVE: Neuromyelitis optica (NMO) is a severe autoimmune disorder of the central nervous system (CNS) characterized by aquaporin-4 antibody (AQP4-IgG)-mediated astrocyte injury. IL-1β-mediated inflammatory signaling plays a critical role in amplifying astrocyte damage and propagating CNS inflammation in NMO. However, the astrocyte-intrinsic mechanisms linking IL-1β signaling to downstream pathways, such as STING activation, remain poorly understood. To address this knowledge gap, in this study, we aim to elucidate the astrocyte-intrinsic mechanisms, specifically the IL-1β-IL-1R STING signaling axis, that contribute to NMO pathogenesis, and to evaluate the therapeutic potential of IL-1β-targeting antisense oligonucleotides (ASOs). METHODS: Using a multi-level experimental system comprising in vitro primary astrocytes, ex vivo organotypic cerebellar slices, and in vivo NMO mouse models, we systematically investigated the critical role of the astrocytic IL-1β-IL-1R STING signaling axis in NMO pathogenesis. Utilizing diverse interventions-including an IL-1β-neutralizing antibody, astrocyte-specific IL-1β knockout, the IL-1R inhibitor Anakinra, STING genetic ablation, and IL-1β ASOs-in conjunction with behavioral, histopathological, and molecular analyses, we comprehensively delineated the impact of this signaling pathway on NMO pathology. These data support the translation of targeted therapeutic strategies. RESULTS: IL-1β signals through the IL-1 receptor (IL-1R) to induce STING-dependent proinflammatory cytokine production in astrocytes. This inflammatory cascade can be suppressed by the IL-1R antagonist anakinra or genetic ablation of STING. Therapeutic administration of lead IL-1β targeting ASO reduces IL-1β expression, preserves AQP4 levels and myelin integrity, and improves functional outcomes. INTERPRETATION: The IL-1β-IL-1R STING signaling axis is a central contributor to NMO pathogenesis and supports IL-1β ASO therapy as a promising potential disease-modifying approach. ANN NEUROL 2026.