Chenodeoxycholic acid activates NLRP3 inflammasome and contributes to cholestatic liver fibrosis

Dec 8, 2016Oncotarget

Chenodeoxycholic acid triggers inflammation and may contribute to liver scarring in bile flow blockage

AI simplified

Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

Chenodeoxycholic acid (CDCA) could dose-dependently activate the NLRP3 inflammasome and promote inflammation in macrophages.

Excessive bile acids in the liver are linked to cholestatic liver injury and inflammation.
CDCA induces the release of the inflammatory cytokine IL-1β from macrophages.
Activation of the NLRP3 inflammasome by CDCA is associated with increased production of reactive oxygen species (ROS) and potassium ion efflux.
CDCA triggers ROS formation through specific signaling pathways involving TGR5 and EGFR.
Inhibition of the NLRP3 inflammasome in a mouse model reduced inflammation and liver fibrosis.

AI simplified

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.

Full Text

We can’t show the full text here under this license. Use the link below to read it at the source.

View full text ↗

Chenodeoxycholic acid activates NLRP3 inflammasome and contributes to cholestatic liver fibrosis

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief

Abstract

Full Text

Related papers

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief