TRPM2-mediated extracellular Ca2+ entry promotes acinar cell necrosis in biliary acute pancreatitis.

Abstract

Acute biliary pancreatitis is a significant clinical challenge as currently no specific pharmaceutical treatment exists. Intracellular Ca2+ overload, increased reactive oxygen species (ROS) production, mitochondrial damage and intra-acinar digestive enzyme activation caused by bile acids are hallmarks of acute biliary pancreatitis. Transient receptor potential melastatin 2 (TRPM2) is a non-selective cation channel that has recently emerged as an important contributor to oxidative-stress-induced cellular Ca2+ overload across different diseases. We demonstrated that TRPM2 is expressed in the plasma membrane of mouse pancreatic acinar and ductal cells, which can be activated by increased oxidative stress induced by H2 O2 treatment and contributed to bile acid-induced extracellular Ca2+ influx in acinar cells, which promoted acinar cell necrosis in vitro and in vivo. These results suggest that the inhibition of TRPM2 may be a potential treatment option for biliary pancreatitis. Acute biliary pancreatitis poses a significant clinical challenge as currently no specific pharmaceutical treatment exists. Disturbed intracellular Ca2+ signalling caused by bile acids is a hallmark of the disease, which induces increased reactive oxygen species (ROS) production, mitochondrial damage, intra-acinar digestive enzyme activation and cell death. Because of this mechanism of action, prevention of toxic cellular Ca2+ overload is a promising therapeutic target. Transient receptor potential melastatin 2 (TRPM2) is a non-selective cation channel that has recently emerged as an important contributor to oxidative-stress-induced cellular Ca2+ overload across different diseases. However, the expression and possible functions of TRPM2 in the exocrine pancreas remain unknown. Here we found that TRPM2 is expressed in the plasma membrane of mouse pancreatic acinar and ductal cells, which can be activated by increased oxidative stress induced by H2 O2 treatment. TRPM2 activity was found to contribute to bile acid-induced extracellular Ca2+ influx in acinar cells, but did not have the same effect in ductal cells. The generation of intracellular ROS in response to bile acids was remarkably higher in pancreatic acinar cells compared to isolated ducts, which can explain the difference between acinar and ductal cells. This activity promoted acinar cell necrosis in vitro independently from mitochondrial damage or mitochondrial fragmentation. In addition, bile-acid-induced experimental pancreatitis was less severe in TRPM2 knockout mice, whereas the lack of TRPM2 had no protective effect in cerulein-induced acute pancreatitis. Our results suggest that the inhibition of TRPM2 may be a potential treatment option for biliary pancreatitis.