1. Academic Validation
  2. Blockade of C5aR1 alleviates liver inflammation and fibrosis in a mouse model of NASH by regulating TLR4 signaling and macrophage polarization

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

  • J Gastroenterol. 2023 May 25. doi: 10.1007/s00535-023-02002-w.
Keqing Jiang # 1 2 3 Shibang Lu # 1 2 Dongxiao Li 1 2 Mingjiang Liu 2 Hu Jin 2 Biao Lei 1 2 Sifan Wang 2 Kang Long 1 2 Songqing He 1 2 3 Fudi Zhong 4 5 6
Affiliations

Affiliations

  • 1 Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China.
  • 2 Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Guangxi Medical University, Nanning, 530021, China.
  • 3 Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, 530021, China.
  • 4 Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China. andy020@126.com.
  • 5 Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Guangxi Medical University, Nanning, 530021, China. andy020@126.com.
  • 6 Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, 530021, China. andy020@126.com.
  • # Contributed equally.
Abstract

Background: Nonalcoholic steatohepatitis (NASH) is an advanced form of chronic fatty liver disease, which is a driver of hepatocellular carcinoma. However, the roles of the C5aR1 in the NASH remain poorly understood. Here, we aimed to investigate the functions and mechanisms of the C5aR1 on hepatic inflammation and fibrosis in murine NASH model.

Methods: Mice were fed a normal chow diet with corn oil (ND + Oil), a Western diet with corn oil (WD + Oil) or a Western diet with carbon tetrachloride (WD + CCl4) for 12 weeks. The effects of the C5a-C5aR1 axis on the progression of NASH were analyzed and the underlying mechanisms were explored.

Results: Complement factor C5a was elevated in NASH mice. C5 deficiency reduced hepatic lipid droplet accumulation in the NASH mice. The hepatic expression levels of TNFα, IL-1β and F4/80 were decreased in C5-deficient mice. C5 loss alleviated hepatic fibrosis and downregulated the expression levels of α-SMA and TGFβ1. C5aR1 deletion reduced inflammation and fibrosis in NASH mice. Transcriptional profiling of liver tissues and KEGG pathway analysis revealed that several pathways such as Toll-like Receptor signaling, NFκB signaling, TNF signaling, and NOD-like receptor signaling pathway were enriched between C5aR1 deficiency and wild-type mice. Mechanistically, C5aR1 deletion decreased the expression of TLR4 and NLRP3, subsequently regulating macrophage polarization. Moreover, C5aR1 antagonist PMX-53 treatment mitigated the progression of NASH in mice.

Conclusions: Blockade of the C5a-C5aR1 axis reduces hepatic steatosis, inflammation, and fibrosis in NASH mice. Our data suggest that C5aR1 may be a potential target for drug development and therapeutic intervention of NASH.

Keywords

C5aR1; Complement factor C5a; Macrophage polarization; Nonalcoholic steatohepatitis; Toll-like receptor signaling pathway.

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