The IL-1β-STING Signaling Axis Drives Neuromyelitis Optica Pathogenesis in a Murine Model PMID: 42059549

ADC Targets in Oncology

2026-04-10

The IL-1β-STING Signaling Axis Drives Neuromyelitis Optica Pathogenesis in a Murine Model

Ann Neurol. 2026 Apr 30. doi: 10.1002/ana.78233.

Siyu Han ¹ ² , Ziqi Liang ³ , Chongyou Zhang ² , Siyu Yang ² , Jiade Li ⁴ , Wei Jiang ⁵ ⁶ , Huiming Xu ⁵ , Haoyang Li ⁵ , Xiaoxin Xiang ⁵ , Ruoyi Guo ⁷ ⁸ , Wenjing Luo ⁹ , Bin Li ⁷ ⁸ , Changyong Tang ⁵ , Yuhong Zhang ¹⁰ , Shanshan Yang ¹ , Guangyou Wang ¹ ² ¹¹ ¹² ¹³

Affiliations

1. Department of Neurology, The First Affiliated Clinical Hospital of Harbin Medical University, Harbin, People's Republic of China.
2. Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University, Harbin, People's Republic of China.
3. Institute of Modern Biology, Nanjing University, Nanjing, People's Republic of China.
4. Department of Biotherapy Center, Harbin Medical University Cancer Hospital, Harbin, People's Republic of China.
5. Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.
6. Department of Neurology, Shandong Key Laboratory of Mitochondrial Medicine and Rare Diseases, Research Institute of Neuromuscular and Neurodegenerative Diseases, Qilu Hospital of Shandong University, Jinan, People's Republic of China.
7. Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China.
8. Key Laboratory of Clinical Neurology (Hebei Medical University), Ministry of Education, Shijiazhuang, People's Republic of China.
9. Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China.
10. The Affiliated Brain Hospital, Guangzhou Medical University, Guangzhou, People's Republic of China.
11. Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China.
12. Key Laboratory of Nerve Injury and Immunity of Heilongjiang Province, Harbin, People's Republic of China.
13. Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University), Ministry of Education, Harbin, People's Republic of China.

Abstract

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.