Abstract
Severe acute pancreatitis is a lethal inflammatory disease frequently accompanied by pancreatic necrosis. We aimed to identify a key regulator in the development of pancreatic necrosis. A cytokine/chemokine array using sera from patients with acute pancreatitis (AP) revealed that serum CXCL16 levels were elevated according to the severity of pancreatitis. In a mouse model of AP, Cxcl16 expression was induced in pancreatic acini in the late phase with the development of pancreatic necrosis. Cxcl16−/− mice revealed similar sensitivity as wild-type (WT) mice to the onset of pancreatitis, but better resisted development of acinar cell necrosis with attenuated neutrophil infiltration. A cytokine array and immunohistochemistry revealed lower expression of Ccl9, a neutrophil chemoattractant, in the pancreatic acini of Cxcl16−/− mice than WT mice. Ccl9 mRNA expression was induced by stimulation with Cxcl16 protein in pancreatic acinar cells in vitro, suggesting a Cxcl16/Ccl9 cascade. Neutralizing antibody against Cxcl16 ameliorated pancreatic injury in the mouse AP model with decreased Ccl9 expression and less neutrophil accumulation. In conclusion, Cxcl16 expressed in pancreatic acini contributes to the development of acinar cell necrosis through the induction of Ccl9 and subsequent neutrophil infiltration. CXCL16 could be a new therapeutic target in AP.
Highlights
Severe acute pancreatitis is a lethal inflammatory disease frequently accompanied by pancreatic necrosis
Edematous pancreatitis is a self-limiting disease treated by supportive management and regarded as mild acute pancreatitis (MAP), pancreatic necrosis can provoke local infection and subsequent systemic inflammatory reactions characterized by enhanced cytokine responses: called systemic inflammatory response syndrome or multiple organ dysfunction syndromes
Serum lactate dehydrogenase values were significantly higher in Severe acute pancreatitis (SAP) patients than in MAP patients or controls (p < 0.05), which may be due to greater tissue damage in SAP patients than in MAP patients
Summary
Severe acute pancreatitis is a lethal inflammatory disease frequently accompanied by pancreatic necrosis. In a mouse model of AP, Cxcl[16] expression was induced in pancreatic acini in the late phase with the development of pancreatic necrosis. Cxcl[16] expressed in pancreatic acini contributes to the development of acinar cell necrosis through the induction of Ccl[9] and subsequent neutrophil infiltration. It is generally accepted that the development of pancreatitis depends upon pro-inflammatory cytokine responses secreted by leukocytes accumulated into the inflamed pancreas[8,9]. In Th1-acquired immune responses, CXCL16 functions as a co-stimulatory molecule and its soluble form is a chemoattractant for activated T-cells[22,23,24] In addition to these functions in innate and acquired immunity, CXCL16 can induce downstream gene expressions through various signaling cascades[25,26,27]. How CXCL16 affects the development of necrotizing pancreatitis through its multiple functions, remains unclear
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