Down-regulation of TRPM2 attenuates hepatic ischemia/reperfusion injury through activation of autophagy and inhibition of NLRP3 inflammasome pathway

Aim: Hepatic 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-glucosedeprivation/reoxygenation (OGD/R) induced hepatocyte injury.

Methods: We 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.

Results: We 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.

Conclusions: Downregulation 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.