C5aR1介导缺血再灌注后早期大鼠脑内炎症反应的进展,ACS Chemical Neuroscience

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C5aR1介导缺血再灌注后早期大鼠脑内炎症反应的进展
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2021-10-12 , DOI: 10.1021/acschemneuro.1c00244
Yunwei Shi ₁ , Ying Jin ₁ , Xing Li ₂ , Chen Chen ₁ , Zhihong Zhang ₁ , Xiaoyu Liu ₁ , Yijun Deng ₂ , Xingjuan Fan ₃ , Caiping Wang ₁

Affiliation

C5a 受体 1 (C5aR1) 可诱导对损伤的强烈炎症反应。靶向 C5aR1 已成为一种新的抗炎治疗方法。然而，C5aR1 在脑缺血再灌注（I/R）损伤中的作用及其确切机制尚未阐明。在这里，我们确定了 C5aR1 信号传导是否对缺血后炎症和脑损伤至关重要，以及它是否是在 I/R 损伤后早期使用可溶性受体拮抗剂 PMX53 进行治疗性阻断的有效靶点。在体外模型（氧和葡萄糖剥夺和再灌注，OGD/R）和体内在 I/R 模型（大脑中动脉闭塞和再灌注，MCAO/R）模型中，大鼠神经元细胞 C5aR1 基因表达显着上调，肿瘤坏死因子-α（TNF- α)、白细胞介素-1β (IL-1β) 和 IL-6。PMX53 治疗对 C5aR1 的抑制显着减少了细胞损伤和炎症，并促进了脑功能的恢复。进一步的机制研究表明，PMX53 抑制 C5aR1 通过抑制 TLR4 和 NF-κB 信号通路和减少 TNF-α、IL-1β 和 IL- 的产生来保护大鼠免受 MCAO/R 损伤、减少细胞炎症和细胞凋亡。 6 在 MCAO/R 大鼠中。此外，在体外操纵 C5aR1 基因表达显示包括 TLR4、TNF-α、IL-1β 和 IL-6 在内的炎症级联信号与 C5aR1 表达水平的调节同时受到调节。因此，我们的结果证明了 C5aR1 在 I/R 损伤后脑损伤和炎症反应的进展中的致病作用。我们的研究清楚地表明，C5aR1 抑制可能是缺血性中风的有效治疗策略。

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C5aR1 Mediates the Progression of Inflammatory Responses in the Brain of Rats in the Early Stage after Ischemia and Reperfusion

C5a receptor 1 (C5aR1) can induce a strong inflammatory response to an injury. Targeting C5aR1 has emerged as a novel anti-inflammatory therapeutic method. However, the role of C5aR1 in cerebral ischemia and reperfusion (I/R) injury and the definitive mechanism have not been elucidated clearly. Here, we determined whether C5aR1 signaling was essential to the post-ischemic inflammation and brain injury and whether it is a valid target for therapeutic blockade by using soluble receptor antagonist PMX53 in the early stage after I/R injury. In an in vitro model (oxygen and glucose deprivation and reperfusion, OGD/R) and in vivo model (middle cerebral artery occlusion and reperfusion, MCAO/R) of I/R, the neuronal cells of rats showed significantly up-regulated gene expression of C5aR1, and a notable inflammatory response was demonstrated with elevated tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6. Inhibition of C5aR1 by PMX53 treatment significantly reduced cell injury and inflammation and promoted brain function recovery. Further mechanism studies showed that inhibiting C5aR1 by PMX53 protected the rats from MCAO/R injury, decreased cell inflammation, and apoptosis via inhibiting the TLR4 and NF-κB signaling pathway and reducing the production of TNF-α, IL-1β, and IL-6 in MCAO/R rats. In addition, manipulation of the C5aR1 gene expression in vitro displayed that the inflammatory cascade signals including TLR4, TNF-α, IL-1β, and IL-6 were coincidently regulated with the regulation of C5aR1 expression levels. Thus, our results demonstrated a pathogenic role for C5aR1 in the progression of brain injury and inflammation response following I/R injury. Our study clearly demonstrated that C5aR1 inhibition might be an effective treatment strategy for ischemic stroke.

更新日期：2021-11-03

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