Abstract
Accumulation of hydrophobic bile acids in the liver contributes to cholestatic liver injury. Inflammation induced by excessive bile acids is believed to play a crucial role, however, the mechanisms of bile acids triggered inflammatory response remain unclear. Recent studies have highlighted the effect of NLRP3 inflammasome in mediating liver inflammation and fibrosis. In this study, we for the first time showed that chenodeoxycholic acid (CDCA), the major hydrophobic primary bile acid involved in cholestatic liver injury, could dose-dependently induce NLRP3 inflammasome activation and secretion of pro-inflammatory cytokine-IL-1β in macrophages by promoting ROS production and K+ efflux. Mechanistically, CDCA triggered ROS formation in part through TGR5/EGFR downstream signaling, including protein kinase B, extracellular regulated protein kinases and c-Jun N-terminal kinase pathways. Meanwhile, CDCA also induced ATP release from macrophages which subsequently causes K+ efflux via P2X7 receptor. Furthermore, in vivo inhibition of NLRP3 inflammasome with caspase-1 inhibitor dramatically decreased mature IL-1β level of liver tissue and ameliorated liver fibrosis in bile duct ligation (BDL) mouse model. In conclusion, excessive CDCA may represent an endogenous danger signal to activate NLRP3 inflammasome and initiate liver inflammation during cholestasis. Our finding offers a mechanistic basis to ameliorate cholestatic liver fibrosis by targeting inflammasome activation.
Highlights
Cholestasis is a pathological condition that occurs when bile outflow from the liver is impaired, which presents in multiple disorders including primary biliary cirrhosis, congenital biliary atresia, progressive familial intrahepatic cholestasis, drug hepatotoxicity and other forms of liver disease [1,2,3]
We hypothesized that chenodeoxycholic acid (CDCA) may serve as the danger signal to activate macrophages and provoke the maturation of IL-1β, LPS-primed murine macrophage cell line J774A.1 was incubated with different dosage of CDCA
The mechanisms responsible for the difference between bile acids on the induction of inflammasome activation need further investigation, while one possible explanation is that conjugated bile acids are less hydrophobic, which may be related to their incapability of inducing inflammasome activation
Summary
Cholestasis is a pathological condition that occurs when bile outflow from the liver is impaired, which presents in multiple disorders including primary biliary cirrhosis, congenital biliary atresia, progressive familial intrahepatic cholestasis, drug hepatotoxicity and other forms of liver disease [1,2,3]. Numerous studies indicate that inflammation induced by toxic bile acid retention plays a integral role in the development of liver fibrosis, the molecular www.impactjournals.com/oncotarget mechanism concerning the initiation of inflammatory response during cholestasis still remains unclear [6,7,8,9]. Liver is a major target organ of gut-derived bacteria and endotoxins, which could be promptly eradicated under the physiological conditions, whereas cholestasis is usually accompanied by increased translocation rate of bacteria and endotoxins (such as LPS) due to the intestinal microecological unbalance and mucosal barrier damage caused by bile acids deficiency in the gut, translocated LPS may provide the first signal for the synthesis of pro-IL-1β. Whether the accumulated toxic bile acid can serve as the danger signal to provoke the activation of inflammasome and subsequent production of mature IL-1β is unknown. We focus our investigation on the role and mechanism of CDCA in the activation of NLRP3 inflammasome, and the effect of inflammasome inhibition on the liver fibrosis in the bile duct ligation (BDL) mouse model
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