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

Acute pancreatitis is a painful and potentially life-threatening inflammatory disorder of the exocrine pancreas. ORAI1, a principal store-operated Ca2+ entry channel, was shown to play a crucial role in the development of acute pancreatitis, but little is known about its cell-specific effects. Here, we showed deletion or inhibition of Orai1 in neutrophils decreased Ca2+ influx and impaired multiple neutrophil functions, including chemotaxis, reactive oxygen species production and neutrophil extracellular traps formation. Mice with neutrophil-specific deletion of Orai1 developed the same degree of localized pancreatic injury after administration of caerulein or retrograde infusion of biliopancreatic duct sodium taurocholate infusion. Mice with neutrophil-, but not pancreas-specific deletion of Orai1 protected against pancreatitis- or sepsis-associated acute lung injury and neutrophil infiltration into the lung; while pancreas-specific deletion of Orai1 decreased localized pancreatic tissue damage and immune cell infiltration and down-regulated pancreatic proinflammatory signals, suggesting cell-specific effects of ORAI1 on modulating tissue damages during acute pancreatitis. Our study further emphasized that systemic administration of ORAI1 inhibitors is a promising therapeutic strategy as an early treatment for acute pancreatitis.