Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong 226001, Jiangsu, China.
Department of ICU, No. 1 People's Hospital of Yancheng City, The Fourth Affiliated Hospital of Nantong University, Yancheng 224000, Jiangsu, China.
ACS Chem Neurosci. 2021 Nov 3;12(21):3994-4006. doi: 10.1021/acschemneuro.1c00244. Epub 2021 Oct 12.
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 model (oxygen and glucose deprivation and reperfusion, OGD/R) and 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 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.
C5a 受体 1（C5aR1）可引起损伤后的强烈炎症反应。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，我们通过在 I/R 损伤后早期使用可溶性受体拮抗剂 PMX53，确定 C5aR1 信号是否对缺血后炎症和脑损伤至关重要，以及它是否是治疗阻断的有效靶点。在氧葡萄糖剥夺再灌注（OGD/R）和大脑中动脉闭塞再灌注（MCAO/R）的 I/R 模型中，大鼠神经元细胞 C5aR1 的基因表达明显上调，并表现出明显的炎症反应，肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）和白细胞介素-6（IL-6）水平升高。PMX53 治疗抑制 C5aR1 可显著减轻细胞损伤和炎症，促进脑功能恢复。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，减少 TNF-α、IL-1β 和 IL-6 在 MCAO/R 大鼠中的产生，从而保护大鼠免受 MCAO/R 损伤，减少细胞炎症和凋亡。此外，C5aR1 基因表达的操作显示，包括 TLR4、TNF-α、IL-1β 和 IL-6 在内的炎症级联信号与 C5aR1 表达水平的调节一致。因此，我们的结果表明 C5aR1 在 I/R 损伤后脑损伤和炎症反应的进展中具有致病作用。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。
