Elsevier

Redox Biology

Volume 55, September 2022, 102404
Redox Biology

Inhibition of NLRP3-mediated crosstalk between hepatocytes and liver macrophages by geniposidic acid alleviates cholestatic liver inflammatory injury

https://doi.org/10.1016/j.redox.2022.102404Get rights and content
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Abstract

The excessive accumulation of bile acids (BA) in hepatocytes can trigger inflammatory response and recruit macrophages, thereby accelerating cholestatic liver injury. The crosstalk between hepatocytes and macrophages has been recently implicated in the pathogenesis of cholestasis; however, the underlying mechanisms remain unclear. Here, we demonstrated that BA initiate NLRP3 inflammasome activation in hepatocytes to release proinflammatory cytokines and promote the communication between hepatocytes and macrophages, thus enhancing liver inflammation in an NLRP3-dependent manner. NLRP3-inhibition by geniposidic acid (GPA), a novel NLRP3-specific covalent inhibitor that directly interacts with NLRP3, in hepatocytes and macrophages abated BA-induced inflammation. Moreover, NLRP3-deletion or its inhibition mitigated ANIT-induced cholestatic inflammation, whereas disrupting the crosstalk between hepatic macrophages and hepatocytes attenuated the hepatoprotective effect of GPA against ANIT-induced cholestatic inflammation. Therefore, blocking this crosstalk by suppressing NLRP3 inflammasome activation may represent a novel therapeutic strategy for cholestasis.

Graphical abstract

NLRP3 activation promotes mutual crosstalk between hepatocytes and macrophages to exacerbate bile acid-induced hepatocyte inflammation. Inhibition of NLRP3 activation by blockage of mutual crosstalk between hepatocytes and hepatic macrophages facilitates alleviation of cholestatic liver inflammatory injury.

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GPA attenuates inflammation by mediating Hepatocytes-Macrophages crosstalk via the inhibition of NLRP3 inflammasome.

Abbreviations

alanine aminotransferase
ALT
α-naphthalene isothiocyanate
ANIT
apoptosis-associated speck-like protein
ASC
aspartate transaminase
AST
β-mercaptoethanol
β-Me
bile acids
BA
bile duct ligation
BDL
biotinylated GPA
bio-GPA
bone-marrow-derived macrophage
BMDM
geniposidic acid
GPA
Kupffer cells
KCs
NOD-like receptor protein 3
NLRP3
primary mouse hepatocytes
PMHs
primary sclerosing cholangitis
PSC
taurocholic acid
TCA
total bile acid
TBA
total bilirubin
TBIL

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