Down-regulation of TRPM2 attenuates hepatic ischemia/reperfusion injury through activation of autophagy and inhibition of NLRP3 inflammasome pathway
Down-regulation of TRPM2 attenuates hepatic ischemia/reperfusion injury through activation of autophagy and inhibition of NLRP3 inflammasome pathway
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TRPM2 的下调通过激活自噬和抑制 NLRP3 炎性体途径减轻肝缺血/再灌注损伤
DOI：
10.1016/j.intimp.2021.108443
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发表时间：
2022
影响因子：
5.6
通讯作者：
Ma Yi
中科院分区：
文献类型：
--
作者：
Zhang Tao;Huang Wenqi;Ma Yi
目的肝缺血/再灌注（I/R）损伤是一种重要的病理过程，导致高发病率和死亡率，但其潜在机制尚不清楚。最近的研究表明，瞬时受体电位melastatin 2 (TRPM2)在器官I/R损伤中发挥着关键作用，但其确切机制尚不清楚。本研究探讨了TPRM2在肝I/R损伤和氧糖剥夺/复氧(OGD/R)诱导的肝细胞损伤中的作用和机制。方法我们使用肝I/R敲除小鼠模型评估TRPM2对肝I/R损伤的影响。在肝细胞 OGD/R 模型中，我们使用自噬激动剂和抑制剂以及 NLRP3 抑制剂研究了 TPRM2 在其中的机制。结果我们发现，敲除 TRPM2 可以防止肝 I/R，同时伴随着自噬激活和 NLRP3 炎性体途径抑制。此外，增加自噬可减轻 OGD/R 诱导的细胞损伤，敲低 TRPM2 可通过激活自噬减轻损伤。此外，我们检测了经过自噬激动剂和抑制剂处理的OGD/R诱导的肝细胞中NLRP3炎症小体通路的表达，发现自噬负向调节NLRP3炎症小体通路。此外，我们发现NLRP3抑制剂INF39的施用增加了OGD/R处理的肝细胞中的细胞活力并导致细胞死亡减少。结论TRPM2的下调可以保护肝脏免受I/R损伤和OGD/R诱导的损伤，这是通过自噬激活和抑制NLRP3炎症小体途径介导的，而自噬在此过程中负向调节NLRP3炎症小体途径。
AimHepatic ischemia/reperfusion (I/R) injury is a significant pathological process that contributes to high morbidity and mortality rates, although the underlying mechanism is unknown. Recent studies have shown that transient receptor potential melastatin 2 (TRPM2) plays a critical role in organ I/R injury, but the exact mechanism is elusive. This study investigates the role and mechanism of TPRM2 in hepatic I/R injury and oxygen-glucose deprivation/reoxygenation (OGD/R) induced hepatocyte injury.MethodsWe evaluated the effects of TRPM2 on hepatic I/R injury using a knockout mouse model of hepatic I/R. In a model of OGD/R in hepatocytes, we investigated the mechanism of TPRM2 in it using the autophagy agonist and inhibitor and an NLRP3 inhibitor.ResultsWe discovered that knockout of TRPM2 protected against hepatic I/R accompanied by autophagy activation and NLRP3 inflammasome pathway inhibition. Furthermore, increasing autophagy attenuated OGD/R-induced cell injury and knockdown of TRPM2 alleviated the injury by activating autophagy. Additionally, we detected the expression of NLRP3 inflammasome pathway in the OGD/R-induced hepatocytes which had been treated with the autophagy agonist and inhibitor, and found that autophagy negatively regulated the NLRP3 inflammasome pathway. Moreover, we discovered that the administration of NLRP3-inhibitor INF39 increased cell viability and caused a decline in cell death in the OGD/R-treated hepatocytes.ConclusionsDownregulation of TRPM2 protected the liver against I/R injury and OGD/R induced injury, mediated by autophagy activation and inhibition of the NLRP3 inflammasome pathway, whereas autophagy negatively regulated the NLRP3 inflammasome pathway in this process.