2. Academic Validation
  3. Microglial STING activation promotes neuroinflammation and pathological changes in experimental mice with intracerebral haemorrhage

Microglial STING activation promotes neuroinflammation and pathological changes in experimental mice with intracerebral haemorrhage

  • Acta Pharmacol Sin. 2025 Apr 8. doi: 10.1038/s41401-025-01540-8.
Yu-Xiao Xue 1 2,  Yi-Jun Chen 2,  Mei-Zhen Qin 2,  Fan-Fan Shang 2,  Yi-Ting Lu 2,  Yu-Hao Sun 1,  Liu-Guan Bian 3,  Ao Zhang 4,  Yang Yu 5,  Chun-Yong Ding 6
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200020, China.
  • 2 Shanghai Frontiers Science Center of Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China.
  • 3 Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200020, China. blg11118@rjh.com.cn.
  • 4 Shanghai Frontiers Science Center of Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China. ao6919zhang@sjtu.edu.cn.
  • 5 Shanghai Frontiers Science Center of Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China. yuyang2011@sjtu.edu.cn.
  • 6 Shanghai Frontiers Science Center of Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China. chunding@sjtu.edu.cn.
PMID: 40200123 DOI: 10.1038/s41401-025-01540-8
Abstract

Neuroinflammation, a significant contributor to secondary brain injury, plays a critical role in the pathological process and prognosis of intracerebral haemorrhage (ICH). Thus, developing interventions to mitigate secondary neuroimmune deterioration is of paramount importance. Currently, no effective immunomodulatory drugs are available for ICH. The Cyclic GMP-AMP Synthase (cGAS)-stimulator of interferon genes (STING) pathway is a recently identified innate immune-sensing pathway primarily expressed in microglia within the central nervous system (CNS) that has been implicated in the pathophysiology of various neurological diseases. In this study we investigated the role of cGAS-STING pathway in ICH. A collagenase model of ICH was established in mice. Brain tissues were collected on D1 or D3 post-ICH. We observed a significant increase in double-stranded (dsDNA) levels and activation of the cGAS-STING pathway in the perihaematomal region of ICH mice. Administration of a blood brain barrier-permeable STING antagonist H151 (10 mg/kg, i.p.) significantly decreased cell Apoptosis, alleviated hematoma growth, and improved motor impairments in ICH mice, accompanied by inhibiting the STING pathway in microglia, reducing production/release of the cGAS-STING pathway downstream inflammatory factors, NLRP3 inflammasome activation and gasdermin D (GSDMD)-induced microglial Pyroptosis. Microglial STING conditional knockout significantly mitigated ICH-induced neuroinflammatory responses, pathological damage and motor dysfunction. These results suggest that the microglial STING pathway promotes brain pathological damage and behavioural defects in ICH mice by activating the NLRP3 inflammasome and microglial Pyroptosis. The STING pathway may serve as a potential therapeutic target for ICH-induced secondary brain injury.

Keywords

GSDMD; NLRP3; STING; intracerebral haemorrhage; neuroinflammation; pyroptosis.

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