Purpose: Cholestatic liver injury (CLI) is commonly associated with many hepatobiliary diseases and substantially increases the peri-operative morbidity and mortality in liver surgery and transplantation. Although earlier studies indicated bile acid (BA)-induced apoptosis as the main mechanism of CLI, recent work have shed light on BA-induced sterile inflammation in the pathogenesis of CLI. We hereby explore the role of inflammasome activation in BA-induced hepatic injury and evaluate its value as a potential therapeutic target.

Methods: 6-8 weeks old C57BL/6, Nalp3-/- or Caspase 1-/- mice were subjected to sham operation or bile duct ligation (BDL). In vitro, isolated hepatocytes and Kupffer cells were subjected to various BA stimulation. Western blot and immunohistochemical staining were performed to evaluate the inflammasome activation.

Results: The cleaved form of IL-1β, IL-18, IL-33 and activated caspase-1 were greater in abundance in the liver tissue, reaching their peak at day 7 or 14 post-BDL, suggestive of inflammasome activation within the liver. There was a stepwise increase in the expression of Nalp3, Caspase 1, IL-1β and IL-18 by real-time PCR. We next sought to determine whether targeting the inflammasome complex could ameliorate CLI. BDL in either Nalp3-/- or Caspase 1-/- mice resulted in marked improvement in liver function early after BDL (day 3 and 5), and decreased intrahepatic expression of several inflammatory genes compared with WT littermates. Consistently, treatment of BDL mice with omega-3 poly-unsaturated fatty acids or the traditional Chinese herbal preparation Xuebijing to interfere with inflammasome activation effectively lessened the CLI. In vitro culture of isolated hepatocytes or Kupffer cells in the presence of various BAs resulted in overt inflammasome activation, with GCDC having the most dramatic effects. Further mechanistic studies revealed GCDC potently suppressed autophage, which facilitated the generation of intracellular reactive oxygen species (ROS) and caused activation of inflammasome.

Conclusion: Our study highlights the important role of inflammasome activation in the pathogenesis of cholestasis, targeting inflammasome activation may be exploited as novel therapeutic means in the management of CLI.

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