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Orai1 in pancreatic ductal cells mediates pancreas-intestinal crosstalk in experimental acute pancreatitis via the secretion of antimicrobial peptide REG3B in pancreatic juice

ABSTRACT: Pancreatic ductal epithelial cells (PDECs) play a crucial role in the development of acute pancreatitis (AP). We and others have previously shown that Orai1 inhibitor confers protection against AP severity. In this study, we aim to investigate the effect and the underlying mechanisms of Orai1 in PDECs on experimental AP and its-associated intestinal damage. We found that Orai1 deletion in PDECs markedly mitigated the prolonged elevation of calcium and preserved the decreased mitochondrial membrane potential due to sodium taurocholate (NaT) or palmitoleic acid (POA) exposure. PDECs-specific Orai1 deletion notably lessened pancreatitis severity and restored the impaired pancreatic juice secretion during AP. Increased expression of tight junction proteins and decreased intestinal permeability and inflammation were observed in duodenal and colonic tissue of PDECs-specific Orai1 knockout mice. Furthermore, the deletion of Orai1 protected against pancreatitis-associated dysbiosis in the duodenum, but not in the colon. Mechanically, this protective effect was partially attributed to the enhanced secretion of REG3B in pancreatic juice during AP. Finally, intraperitoneal administration of REG3B partially alleviated AP severity and pancreatitis-associated intestinal injury and inflammation. Collectively, these findings suggest that Orai1 inhibitor may serve as potential therapeutic strategy for the management of AP and associated intestinal injury.

ORGANISM(S): Mus musculus

PROVIDER: GSE285771 | GEO | 2026/01/07

REPOSITORIES: GEO

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Project description:Acute pancreatitis (AP), a severe inflammatory disorder of the pancreas, lacks effective pharmacological treatment. The disease is primarily driven by necrosis of pancreatic acinar cells (PACs), which intensifies inflammation and organ injury. This study explores the potential of BCL2 inhibitors, specifically Navitoclax and Venetoclax, to shift cell death pathways from necrosis to apoptosis and thereby mitigate disease severity. Ex vivo models using cerulein or ethanol/palmitoleic acid (EtOH/POA) showed that both inhibitors significantly reduced necrosis, increased apoptosis, and improved PAC viability and ATP levels. In mouse models of AP, both drugs promoted apoptosis and decreased tissue necrosis, with Venetoclax showing superior efficacy and safety. Venetoclax markedly reduced disease severity in two AP models without affecting healthy tissue or inducing thrombocytopenia. In contrast, Navitoclax caused apoptosis even in healthy tissue and triggered thrombocytopenia. Importantly, both drugs attenuated pathological Ca2+ responses in PACs and upregulated the expression of Ca²⁺-binding proteins S100A8/A9 and the chemokine CCL8. The latter may mediate enhanced apoptotic clearance and limit secondary necrosis, supporting the therapeutic shift from necrosis to apoptosis. Proteomic analyses revealed extensive drug-induced remodeling. In the short-term AP model, both inhibitors altered expression of proteins linked to intracellular compartments and extracellular signaling, reflecting cellular adaptation. In CP, Navitoclax strongly upregulated ECM and lysosomal proteins while downregulating ribosomal components – indicating intensified fibrosis and suppressed protein synthesis. Venetoclax had milder effects and did not worsen fibrosis. Despite Navitoclax’s efficacy toward activated pancreatic stellate cells in vitro, it exacerbated fibrosis and tissue atrophy in CP in vivo, likely due to ongoing parenchymal damage and stellate cell activation. Together, these findings demonstrate that selective BCL2 inhibition with Venetoclax promotes apoptosis, reduces necrosis, and improves outcomes in AP, supporting its repurposing as a therapeutic strategy. However, BCL2 inhibition does not benefit CP and may aggravate fibrosis, underscoring the need for context-specific approaches.

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Orai1 in pancreatic ductal cells mediates pancreas-intestinal crosstalk in experimental acute pancreatitis via the secretion of antimicrobial peptide REG3B in pancreatic juice

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