Claudin-2 limits pancreatitis development through regulating tight junction-controlled pancreatic ductal transport

Abstract

ABSTRACTChronic pancreatitis is a chronic, progressive inflammatory disease that results in irreversible scarring and a reduction in pancreatic function. This disease has multifactorial origins, involving both environmental risks like diet, alcohol, and smoking, as well as genetic predispositions. Genome-wide association studies (GWAS) identified polymorphisms at the X-linked claudin-2 locus as risk factors for both sporadic and alcohol-related chronic pancreatitis.CLDN2encodes claudin-2, a paracellular cation-selective channel localized at tight junctions and expressed in the pancreas and other secretory organs. However, if and how claudin-2 may modify pancreatitis susceptibility remain poorly understood. We aimed to clarify the potential role of claudin-2 in the onset and progression of pancreatitis.We employed multiple methodologies, including examining human pancreatic tissue, using the caerulein-induced experimental pancreatitis mouse model, along with normal pancreatic ductal epithelial cell based organoid transport studies. In both human chronic pancreatitis tissues and in a caerulein-induced experimental pancreatitis model, claudin-2 protein is significantly upregulated in pancreatic ductal epithelial cells. Genetically modified mice that lack claudin-2 expression develop more severe experimental pancreatitis, indicating claudin-2 plays a protective role in pancreatitis development. Our organoid based studies further demonstrate claudin-2 is critical for both sodium-dependent water transport and cAMP-dependent fluid secretion in pancreatic ductal epithelium. These findings suggest that intact claudin-2 function is essential for homeostatic and induced fluid transport, which may protect against severe pancreatitis by adjusting pancreatic ductal secretion to prevent worsening autodigestion and inflammation.In conclusion, our studies suggest claudin-2 upregulation during pancreatitis may play a protective role for disease development, and decreased claudin-2 function may increase pancreatitis severity. These results point to the possibility of modulating pancreatic ductal claudin-2 function as an approach for pancreatitis therapy.