GPR35通过与Raf1的CR2结构域结合来保护缺血性卒中患者免受再灌注损伤
GPR35 protects against reperfusion injury in ischemic stroke by binding with the CR2 domain of Raf1.
摘要(中文译文)
缺血性中风仍然是全球死亡和残疾的主要原因。虽然及时血管再通是脑缺血最直接和临床验证的干预措施，但再灌注通常会导致继发性脑损伤，神经炎症起着核心作用。来自缺血性中风小鼠模型的单细胞测序数据表明，G蛋白偶联受体35（GPR35）是缺血后炎症反应的潜在调节因子。在体内脑缺血再灌注模型和体外氧糖剥夺系统中，GPR35表达显著增加，主要定位于小胶质细胞。功能研究表明，小鼠脑组织中GPR35的基因敲除显著加剧了动物模型中的脑梗死体积、神经功能缺损和神经炎症，而GPR35的过表达产生了治疗作用。一致地，使用扎普司特对GPR35进行药理学激活可以减轻缺血再灌注损伤，减少促炎细胞因子的产生。从机制上讲，扎普司特介导的GPR35激活通过调节Raf1/ERK1/2/MAPK信号级联抑制了促炎细胞因子的产生。值得注意的是，Raf1敲除减轻了梗死周围区域GPR35缺乏引起的病理恶化。共免疫沉淀分析揭示了GPR35和Raf1之间的直接相互作用，其中CR2结构域是Raf1自抑制的关键区域，被确定为主要结合界面。总的来说，这些发现表明，扎普利司特通过激活GPR35，最终减轻梗死进展和神经炎症，在脑缺血再灌注损伤中具有脑保护作用。这一机制见解将GPR35定位为减轻缺血性卒中再灌注损伤的有前景的治疗靶点。
Abstract
Ischemic stroke remains a leading cause of global mortality and disability. While timely vascular recanalization is the most direct and clinically validated intervention for cerebral ischemia, reperfusion often induces secondary brain injury, with neuroinflammation playing a central role. Single-cell sequencing data from an ischemic stroke mouse model identify G protein-coupled receptor 35 (GPR35) as a potential regulator of post-ischemic inflammatory responses. GPR35 expression was markedly increased in both in vivo cerebral ischemia-reperfusion models and in vitro oxygen-glucose deprivation systems, predominantly localizing to microglia. Functional studies revealed that genetic knockdown of GPR35 in murine brain tissue significantly exacerbated cerebral infarction volume, neurological deficits, and neuroinflammation in animal models, whereas GPR35 overexpression produced therapeutic effects. Consistently, pharmacological activation of GPR35 using zaprinast attenuated ischemia-reperfusion injury and reduced proinflammatory cytokine production. Mechanistically, zaprinast-mediated GPR35 activation suppressed proinflammatory cytokine production via modulation of the Raf1/ERK1/2/MAPK signaling cascade. Notably, Raf1 knockdown attenuated the pathological exacerbation induced by GPR35 deficiency in peri-infarct regions. Co-immunoprecipitation analyses revealed a direct interaction between GPR35 and Raf1, with the CR2 domain, a critical region for Raf1 autoinhibition, identified as the primary binding interface. Collectively, these findings demonstrate that zaprinast confers cerebroprotective effects in cerebral ischemia-reperfusion injury by activating GPR35, ultimately attenuating infarct progression and neuroinflammation. This mechanistic insight positions GPR35 as a promising therapeutic target for mitigating reperfusion injury in ischemic stroke.
如何引用
AMA
Xiaojun Li, Qi Wang, Qingyu Cheng, Jingyong Zhou, Tingting Qu, Jianling Xu, et al. GPR35 protects against reperfusion injury in ischemic stroke by binding with the CR2 domain of Raf1.. Journal of neuroinflammation. 2026; doi:10.1186/s12974-026-03726-1.
APA
Xiaojun Li, Qi Wang, Qingyu Cheng, Jingyong Zhou, Tingting Qu, Jianling Xu, et al (2026). GPR35 protects against reperfusion injury in ischemic stroke by binding with the CR2 domain of Raf1.. Journal of neuroinflammation. https://doi.org/10.1186/s12974-026-03726-1
GB/T 7714
Xiaojun Li, Qi Wang, Qingyu Cheng, Jingyong Zhou, Tingting Qu, Jianling Xu, et al. GPR35 protects against reperfusion injury in ischemic stroke by binding with the CR2 domain of Raf1.[J]. Journal of neuroinflammation, 2026 doi:10.1186/s12974-026-03726-1.
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