Blockade of C5aR1 alleviates liver inflammation and fibrosis in a mouse model of NASH by regulating TLR4 signaling and macrophage polarization

• DOI: 10.1007/s00535-023-02002-w
• Publication Date: 2023-05-25T05:01:38Z
• Authors: Keqing Jiang; Shibang Lu; Dongxiao Li; Mingjiang Liu; Hu Jin; Biao Lei; Sifan Wang; Kang Long; Songqing He; Fudi Zhong
• Keywords: Hepatic fibrosis; Macrophage polarization; Steatohepatitis; Steatosis

Abstract Background Nonalcoholic steatohepatitis (NASH) is an advanced form of chronic fatty liver disease, which a driver hepatocellular carcinoma. However, the roles C5aR1 in NASH remain poorly understood. Here, we aimed to investigate functions and mechanisms on hepatic inflammation fibrosis murine model. Methods Mice were fed normal chow diet with corn oil (ND + Oil), Western (WD Oil) or carbon tetrachloride CCl 4 ) for 12 weeks. The effects C5a–C5aR1 axis progression analyzed underlying explored. Results Complement factor C5a was elevated mice. C5 deficiency reduced lipid droplet accumulation expression levels TNFα, IL-1β F4/80 decreased C5-deficient loss alleviated downregulated α-SMA TGFβ1. deletion Transcriptional profiling tissues KEGG pathway analysis revealed that several pathways such as Toll-like receptor signaling, NFκB TNF NOD-like signaling enriched between wild-type Mechanistically, TLR4 NLRP3, subsequently regulating macrophage polarization. Moreover, antagonist PMX-53 treatment mitigated Conclusions Blockade reduces steatosis, inflammation, Our data suggest may be potential target drug development therapeutic intervention NASH.