Mechanism Of IL-18 Exacerbates Pancreatic Fibrosis By Promoting The Secretion Of IL-4 From Pancreatic Stellate Cells

Backgroud&Objects: Chronic pancreatitis(CP)is a chronic inflammatory disease that causes pancreatic acinar cells(PACs)injury and pancreatic fibrosis for various reasons,which seriously affects the quality of life of patients,and is significantly associated with an increased risk of pancreatic cancer.As the initial factor of CP,PACs damage is of great significance to the development of CP.Studies have shown that NLRP3 inflammatory body mediated pyroptosis plays an important role in CP,but its mechanism is still unclear.The relationship between IL-18,as a downstream factor of inflammatory corpuscles,and CP pancreatic fibrosis and activation of pancreatic stellate cells(PSCs)deserves further study,which will provide guidance for finding clinical CP related therapeutic targets.Methods: In this study,the mouse pancreatitis model was established by using the method of cerulein and the relatively new method of partial pancreatic duct ligation.Because there were few studies on pancreatic duct ligation model,we made models at various time points to explore the best time points of the CP mouse model and the correlation with clinical CP.The differences between the IL-18 receptor knockout CP mice,C57BL6/J wild-type CP mice and the control group were detected by morphological methods,immunofluorescence and molecular biological methods,and the relevant pathological changes of pancreatic tissue in patients with clinical CP were detected.The role of IL-18/IL-18 R in CP was studied by culturing PSCs in vitro.Results: In the mouse model of pancreatitis induced by partial pancreatic duct ligation,pancreatic pathological score,TNF-α The expression of IL-6 and IL-6 increased with time in the early stage of pancreatitis development,and reached the peak in 72 hours after ligation;In the chronic phase,the degree of pancreatic fibrosis reached the peak in 21 days after ligation,and was very similar to the clinical CP.The expression of IL-18 and IL-18 R in human and mouse CP increased,and the pancreatic fibrosis in mice was significantly reduced after IL-18 R knockout.PACs are the main source of IL-18,while IL-18 R is mainly located in PSCs.IL-18 can not directly activate PSCs,but can promote the expression of IL-4 in PSCs.In addition,M2 polarization plays a key role in the progress of CP,and IL-18 R knockout can reduce M2 macrophage level.Conclusions: IL-18 from PACs can combine with IL-18 R on the surface of PSCs to promote the secretion of IL-4 in PSCs,leading to polarization of M2 macrophages,thereby promoting the progression of pancreatic fibrosis.In addition,the optimal time point of CP model induced by partial pancreatic duct ligation is 21 days,which can ideally simulate clinical CP in terms of morphology and immune infiltration characteristics.