Inflammation-Induced Claudin-2 Up-Regulation Limits Pancreatitis Development by Enhancing Pancreatic Ductal Transport

Pancreatitis is influenced by environmental and genetic factors. Genome-wide association studies identified polymorphisms at the X-linked CLDN2 locus as risk factors for chronic pancreatitis. CLDN2 encodes claudin-2 (CLDN2), a paracellular cation-selective channel at tight junctions. However, its role in pancreatitis susceptibility remains unclear. We aimed to determine the role of CLDN2 in pancreatitis onset and progression.

Human pancreatic tissue, pancreatitis mouse models, pancreatic ductal epithelial organoids, and isolated mouse pancreatic ducts were used. CLDN2 expression, its regulation by cytokines, and its impact on pancreatic inflammation, fibrosis, and ductal fluid transport were assessed.

CLDN2 was up-regulated in human chronic pancreatitis and in both caerulein-induced and T7D23A mutation mouse models. Interferon-γ increased CLDN2 expression at RNA and protein levels in organoids and mouse pancreas. Ifng knockout (KO) mice showed reduced caerulein-induced CLDN2 up-regulation compared with wild-type mice. Functionally, Cldn2 KO mice developed more severe disease in both short-term caerulein treatment-induced acute pancreatitis and in a caerulein- and alcohol-treatment induced chronic pancreatitis models. Organoid-based studies revealed CLDN2 is essential for sodium-dependent water transport and adenosine 3',5'-cyclic monophosphate-driven, cystic fibrosis transmembrane conductance regulator-dependent, and 4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid-sensitive fluid secretion. Finally, studies using isolated pancreatic ducts revealed that forskolin-stimulated fluid secretion requires CLDN2. These findings suggest that functional cross talk between paracellular CLDN2 and transcellular transporters is essential for fluid secretion in pancreatic ductal epithelium, protecting against pancreatitis by promoting pancreatic ductal output to limit autodigestion and inflammation.

CLDN2 up-regulation is a pathophysiological response to inflammation, and absence of CLDN2 exacerbates disease severity. Modulating pancreatic ductal CLDN2 function represents a potential therapeutic strategy for pancreatitis.