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Updated: May 1, 2026
Induction of Paralysis and Visual System Injury in Mice by T Cells Specific for Neuromyelitis Optica Autoantigen Aquaporin-4
Published on: August 21, 2017
The IL-1β-STING Signaling Axis Drives Neuromyelitis Optica Pathogenesis in a Murine Model
Siyu Han1,2, Ziqi Liang3, Chongyou Zhang2
1Department of Neurology, The First Affiliated Clinical Hospital of Harbin Medical University, Harbin, People's Republic of China.
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;100:487-510.
