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. 2024 Jan 5:962:176228.
doi: 10.1016/j.ejphar.2023.176228. Epub 2023 Dec 1.

GPR124 induces NLRP3 inflammasome-mediated pyroptosis in endothelial cells during ischemic injury

Yiqian Xu  1 , Xingyue Fang  1 , Zhenqiang Zhao  2 , Haolin Wu  1 , Haofei Fan  2 , Ya Zhang  3 , Qingwen Meng  4 , Qiongwen Rong  2 , Kohji Fukunaga  5 , Qingyun Guo  6 , Qibing Liu  7
Affiliations
Free article

GPR124 induces NLRP3 inflammasome-mediated pyroptosis in endothelial cells during ischemic injury

Yiqian Xu et al. Eur J Pharmacol. .
Free article

Abstract

Objective: G protein-coupled receptor 124 (GPR124) regulates central nervous system angiogenesis and blood-brain barrier (BBB) integrity, and its deficiency aggravates BBB breakdown and hemorrhagic transformation in ischemic mice. However, excessive GPR124 expression promotes inflammation in atherosclerotic mice. In this study, we aimed to elucidate the role of GPR124 in hypoxia/ischemia-induced cerebrovascular endothelial cell injury.

Methods: bEnd.3 cells were exposed to oxygen-glucose deprivation (OGD), and time-dependent changes in GPR124 mRNA and protein expression were evaluated using reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. The effects of GPR124 overexpression or knockdown on the expression of pyroptosis-related genes were assessed at the mRNA and protein levels. Tadehaginoside (TA) was screened as a potential small molecule targeting GPR124, and its effects on pyroptosis-related signaling pathways were investigated. Finally, the therapeutic efficacy of TA was evaluated using a rat model of transient middle cerebral artery occlusion/reperfusion (tMCAO/R).

Results: During OGD, the expression of GPR124 initially increased and then decreased over time, with the highest levels observed 1 h after OGD. The overexpression of GPR124 enhanced the OGD-induced expression of NLRP3, Caspase-1, and Gasdermin D (GSDMD) in bEnd.3 cells, whereas GPR124 knockdown reduced pyroptosis. Additionally, TA exhibited a high targeting ability to GPR124, significantly inhibiting its function and expression and suppressing the expression of pyroptosis-related proteins during OGD. Furthermore, TA treatment significantly reduced the cerebral infarct volume and pyroptotic signaling in tMCAO/R rats.

Conclusions: Our findings suggest that GPR124 mediates pyroptotic signaling in endothelial cells during the early stages of hypoxia/ischemia, thereby exacerbating ischemic injury.

Keywords: Cerebrovascular endothelial cells; G protein-coupled receptor 124; Ischemic injury; Pyroptosis; Tadehaginoside.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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