HMGB1 contributes to pancreatic fibrosis by regulating TLR4-mediated autophagy and the NLRP3 inflammasome pathway in chronic pancreatitis

Abstract

The characteristic pathological change in chronic pancreatitis (CP) is pancreatic fibrosis. In the early stages of CP development, injured acinar cells induce the infiltration of inflammatory cells, followed by pancreatic stellate cell (PSC) activation. Activated PSC induce the deposition of extracellular matrix (ECM) and promote the development of pancreatic fibrosis. High-mobility group Box 1 (HMGB1) is a damage-associated molecular pattern (DAMP) molecule. Although HMGB1 is implicated in several types of fibrotic diseases, its functional role and mechanism in pancreatic fibrosis in CP remain unknown. In this study, a dibutyltin dichloride (DBTC)-induced rat CP model was constructed in vivo. The results revealed that HMGB1 translocates from the nucleus of acinar cells to the cytoplasm and is subsequently released into the extracellular space, thereby promoting the progression of pancreatic fibrosis in CP. PSC was isolated and exposed to varying concentrations of HMGB1 in vitro. Resatorvid and si-TLR4 were applied to verify that the functions of HMGB1 were realized by combining with TLR4. 3-MA, si-Atg5 and MCC950 were used to determine the effect of HMGB1 on PSC activation through the regulation of autophagy and the NLRP3 inflammasome. These results indicated that exogenous administration of HMGB1 induces PSC activation and ECM deposition through its receptor TLR4. Mechanistically, the HMGB1/TLR4 axis promoted PSC activation by promoting autophagy–NLRP3 inflammasome activation. Our study highlights the profibrotic role of HMGB1 and provides a novel therapeutic target for the treatment of CP.