NLRP3 Inflammasome Activation‐Induced Acute Papillitis as a Trigger of Acute Pancreatitis ‐ A Novel Mechanism of Microlithiasis‐Induced Acute Pancreatitis

ABSTRACT Introduction Obstruction of the pancreatic duct by impacted gallstones at the level of the papilla vateri causes acute pancreatitis. How non‐obstructing stones such as microlithiasis or sludge cause pancreatitis has not been studied. We aimed to understand the pathomechanism of microlithiasis‐induced acute pancreatitis. Methods In human papillary biopsies from patients with microlithiasis‐induced acute pancreatitis ( n = 4), alcohol‐induced acute pancreatitis ( n = 5), and control subjects without pancreatobiliary disease ( n = 4), the inflammatory infiltrate was quantified. Bone marrow–derived macrophages generated from C57BL/6 mice were treated in vitro with cholesterol monohydrate and calcium bilirubinate crystals, and NLRP3 inflammasome‐mediated macrophage activation was quantified. Microlithiasis formation in the gallbladder was induced in mice through lithogenic high fat diet and devazepide. Acute pancreatitis was induced by supramaximal caerulein stimulation. Microlithiasis ejection from the gallbladder was achieved through low‐dose caerulein i.p. Injections. Pancreatitis severity was compared between caerulein‐induced pancreatitis and caerulein‐induced pancreatitis after repetitive microlithiasis ejection. Results Significantly higher infiltration of CD45‐positive leukocytes and increased NLRP3 expression were observed in papillary biopsies from patients with microlithiasis‐induced acute pancreatitis compared with patients with alcohol‐induced acute pancreatitis and control subjects. In line with this, significantly higher IL‐1ß secretion and caspase‐1 activation were observed in vitro in bone marrow‐derived macrophages stimulated with cholesterol monohydrate and calcium billirubinate crystals. In vivo microlithiasis formation was achieved in all mice with high fat diet and devazepide. Compared to caerulein‐induced pancreatitis, in caerulein + microlithiasis pancreatitis, higher LDH, GPT and ALP levels in serum were observed, but without an impact on pancreatitis severity. However, mice papilla mimicked the phenotype of microlithiasis‐induced acute pancreatitis in humans. Conclusion We propose a novel mechanism in which biliary microlithiasis induces a local inflammatory reaction at the papilla (acute papillitis) via NLRP3 inflammasome activation driven by bone marrow‐derived macrophages, without causing pancreatic outflow obstruction.