Bile Acids Activate NLRP3 Inflammasome, Promoting Murine Liver Inflammation or Fibrosis in a Cell Type-Specific Manner

Abstract

Bile acids (BA) as important signaling molecules are considered crucial in development of cholestatic liver injury, but there is limited understanding on the involved cell types and signaling pathways. The aim of this study was to evaluate the inflammatory and fibrotic potential of key BA and the role of distinct liver cell subsets focusing on the NLRP3 inflammasome. C57BL/6 wild-type (WT) and Nlrp3−/− mice were fed with a diet supplemented with cholic (CA), deoxycholic (DCA) or lithocholic acid (LCA) for 7 days. Additionally, primary hepatocytes, Kupffer cells (KC) and hepatic stellate cells (HSC) from WT and Nlrp3−/− mice were stimulated with aforementioned BA ex vivo. LCA feeding led to strong liver damage and activation of NLRP3 inflammasome. Ex vivo KC were the most affected cells by LCA, resulting in a pro-inflammatory phenotype. Liver damage and primary KC activation was both ameliorated in Nlrp3-deficient mice or cells. DCA feeding induced fibrotic alterations. Primary HSC upregulated the NLRP3 inflammasome and early fibrotic markers when stimulated with DCA, but not LCA. Pro-fibrogenic signals in liver and primary HSC were attenuated in Nlrp3−/− mice or cells. The data shows that distinct BA induce NLRP3 inflammasome activation in HSC or KC, promoting fibrosis or inflammation.

Antarctic krill peptide alleviates liver fibrosis via downregulating the secondary bile acid mediated NLRP3 signaling pathway

“…24 Holtmann et al found distinct bile acid induced NLRP3 inflammasome activates of HSCs, promoting fibrosis or inflammation. 46 By comparison, LCA feeding led to the most severe liver damage and activation of the NLRP3 inflammasome. The tracing studies have shown that liver damage and HSC activation were ameliorated in NLRP3 deficient cells or mice.…”

Intestinal Barrier and Permeability in Health, Obesity and NAFLD

“…Liver fibrosis was promoted by DCA feeding, with an upregulation in NLRP3 in primary hepatic stellate cells. These signals, however, were decreased in Nlrp3−/− mice or cells [ 576 ].…”

Bile Acids in Intrahepatic Cholestasis of Pregnancy

“…Elevated levels of BAs induce the production of pro-inflammatory mediators in hepatocytes, attracting immune cells and initiating inflammation in the liver, eventually leading to cholestatic liver damage [ 15 ]. Furthermore, besides direct cytotoxic liver damage from BAs, oxidative stress and BA-induced mitochondrial damage lead to an inflammatory cascade [ 13 , 16 ]. The NLR family pyrin domain containing 3 (NLRP3) inflammasome in hepatic stellate cells and Kupffer cells is activated by BAs, causing inflammation or fibrosis [ 16 ].…”

“…Furthermore, besides direct cytotoxic liver damage from BAs, oxidative stress and BA-induced mitochondrial damage lead to an inflammatory cascade [ 13 , 16 ]. The NLR family pyrin domain containing 3 (NLRP3) inflammasome in hepatic stellate cells and Kupffer cells is activated by BAs, causing inflammation or fibrosis [ 16 ]. The level of intracellular γ-glutamyl-L-cysteinyl-glycine (GSH), which protects cells against oxidative stress, cell proliferation, and division, is significantly influenced by inflammation and oxidative stress related to cholestasis [ 17 ].…”