Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu 610041, China.
Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu 610041, China.
Brain Res. 2020 Dec 1;1748:147109. doi: 10.1016/j.brainres.2020.147109. Epub 2020 Sep 6.
Sepsis-associated encephalopathy (SAE) is a common complication of severe sepsis. Some studies have suggested that P2X7 receptors, a ligand-gated ion channel receptor subgroup activated by extracellular ATP, plays an important role in cell pyroptosis. However, the role of P2X7 receptors in the development of SAE with pyroptosis and its pathways are still unclear. In this study, we established a juvenile rat model of sepsis by cecal ligation and perforation, and showed that there was a significant increase in P2X7 receptor expression in the cortex of juvenile rats with sepsis. When the P2X7 receptor antagonist was administrated, the pyroptosis and extracellular-signal-regulated kinase (ERK) 1/2 signaling pathway were inhibited, and when the P2X7 receptor agonist was administrated, the pyroptosis and ERK1/2 signaling pathway were further activated. In addition, we also found that the administration of ERK1/2 signaling pathway inhibitor not only weakened downstream pyroptosis, but also caused the inhibition of upstream P2X7 receptor expression. In conclusion, our findings illustrated that the ligand-gated ion channel P2X7 receptor mediates NLRP3/caspase-1-related pyroptosis in cerebral cortex of juvenile rats with sepsis through ERK1/2 signaling pathway and plays a neuroprotective role.
脓毒症相关性脑病（SAE）是严重脓毒症的常见并发症。一些研究表明，P2X7 受体是一种由细胞外 ATP 激活的配体门控离子通道受体亚群，在细胞焦亡中发挥重要作用。然而，P2X7 受体在伴有焦亡的 SAE 发展中的作用及其途径仍不清楚。在这项研究中，我们通过盲肠结扎穿孔术建立了幼鼠脓毒症模型，并表明脓毒症幼鼠大脑皮质中 P2X7 受体表达明显增加。当给予 P2X7 受体拮抗剂时，焦亡和细胞外信号调节激酶（ERK）1/2 信号通路被抑制，而给予 P2X7 受体激动剂时，焦亡和 ERK1/2 信号通路进一步被激活。此外，我们还发现，ERK1/2 信号通路抑制剂的给药不仅减弱了下游的焦亡，还导致了上游 P2X7 受体表达的抑制。总之，我们的研究结果表明，配体门控离子通道 P2X7 受体通过 ERK1/2 信号通路介导 NLRP3/caspase-1 相关的幼鼠脓毒症大脑皮质焦亡，并发挥神经保护作用。
