Blocking cGAS-STING pathway promotes post-stroke functional recovery in an extended treatment window via facilitating remyelination

Munire Maimaiti; Chenhui Li; Mingxing Cheng; Ziwei Zhong; Jiameng Hu; Lei Yang; Lele Zhang; Ze Hong; Jinyi Song; Mingyu Pan; Xiaonan Ma; Shufang Cui; Peng Zhang; Haiping Hao; Chen Wang; Haiyang Hu

doi:10.1016/j.medj.2024.03.018

Blocking cGAS-STING pathway promotes post-stroke functional recovery in an extended treatment window via facilitating remyelination

Med. 2024 Apr 16:S2666-6340(24)00130-2. doi: 10.1016/j.medj.2024.03.018. Online ahead of print.

Authors

Munire Maimaiti¹, Chenhui Li², Mingxing Cheng¹, Ziwei Zhong¹, Jiameng Hu¹, Lei Yang¹, Lele Zhang³, Ze Hong⁴, Jinyi Song¹, Mingyu Pan¹, Xiaonan Ma⁵, Shufang Cui¹, Peng Zhang³, Haiping Hao⁶, Chen Wang⁷, Haiyang Hu⁸

Affiliations

¹ State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China.
² State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China. Electronic address: 1620174384@cpu.edu.cn.
³ Central Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
⁴ School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
⁵ Cellular and Molecular Biology Center, China Pharmaceutical University, Nanjing, China.
⁶ Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism, China Pharmaceutical University, Nanjing, China; School of Pharmacy, China Pharmaceutical University, Nanjing, China.
⁷ State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China. Electronic address: cwang1971@cpu.edu.cn.
⁸ Central Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China; Chongqing Innovation Institute of China Pharmaceutical University, Chongqing, China. Electronic address: haiyanghu@cpu.edu.cn.

PMID: 38663402
DOI: 10.1016/j.medj.2024.03.018

Abstract

Background: Ischemic stroke is a major cause of worldwide death and disability, with recombinant tissue plasminogen activator being the sole effective treatment, albeit with a limited treatment window. The cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) pathway is emerging as the major DNA-sensing pathway to invoke immune responses in neuroinflammatory disorders.

Methods: By performing a series of neurobehavioral assessments, electrophysiological analysis, high-throughput sequencing, and cell-based assays based on the transient middle cerebral artery occlusion (tMCAO) mouse stroke model, we examined the effects and underlying mechanisms of genetic and pharmacological inhibition of the cGAS-STING pathway on long-term post-stroke neurological functional outcomes.

Findings: Blocking the cGAS-STING pathway, even 3 days after tMCAO, significantly promoted functional recovery in terms of white matter structural and functional integrity as well as sensorimotor and cognitive functions. Mechanistically, the neuroprotective effects via inhibiting the cGAS-STING pathway were contributed not only by inflammation repression at the early stage of tMCAO but also by modifying the cell state of phagocytes to facilitate remyelination at the sub-acute phase. The activation of the cGAS-STING pathway significantly impeded post-stroke remyelination through restraining myelin debris uptake and degradation and hindering oligodendrocyte differentiation and maturation.

Conclusions: Manipulating the cGAS-STING pathway has an extended treatment window in promoting long-term post-stroke functional recovery via facilitating remyelination in a mouse stroke model. Our results highlight the roles of the cGAS-STING pathway in aggregating stroke pathology and propose a new way for improving functional recovery after ischemic stroke.

Funding: This work was primarily funded by the National Key R&D Program of China.

Keywords: Pre-clinical research; STING antagonist; cGAS-STING pathway; ischemic stroke; phagocyte; remyelination.