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RIP3 deficiency alleviates liver fibrosis by inhibiting ROCK1-TLR4-NF-κB pathway in macrophages

Song Wei1, Haoming Zhou2,3, Qi Wang2,3

  • 1School of Medicine, Southeast University, Nanjing, China.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|July 12, 2019
PubMed

Insights

Receptor-interacting protein 3 (RIP3) in macrophages promotes liver fibrosis. Inhibiting RIP3 in macrophages reduces liver inflammation and fibrosis by blocking the ROCK1-TLR4-NF-κB pathway, suggesting RIP3 as a therapeutic target.

Area of Science:

  • Immunology
  • Hepatology
  • Molecular Biology

Background:

  • Liver fibrosis is a significant pathological process in liver injury.
  • Receptor-interacting protein 3 (RIP3) is implicated in various diseases, but its role in macrophage-mediated liver fibrosis is unknown.
  • RIP3 expression is elevated in liver tissues and macrophages during liver fibrosis.

Purpose of the Study:

  • To investigate the role of RIP3 in macrophages in the development of liver fibrosis.
  • To elucidate the underlying molecular mechanisms involving RIP3 in liver fibrosis.
  • To assess the therapeutic potential of targeting RIP3 in liver fibrosis.

Main Methods:

  • Assessed RIP3 expression in human and mouse liver tissues and macrophages.
  • Utilized mouse models of liver fibrosis (carbon tetrachloride and bile duct ligation) with and without RIP3 in macrophages.
  • Investigated the involvement of the ROCK1-TLR4-NF-κB signaling pathway.
  • Performed experiments involving the infusion of ROCK1-overexpressed macrophages into RIP3-deficient mice.

Main Results:

  • RIP3 expression was upregulated in fibrotic liver tissues and macrophages.
  • Absence of RIP3 in macrophages attenuated inflammation and immune cell accumulation in mouse models.
  • RIP3 deficiency in macrophages significantly reduced CCl4- and BDL-induced liver fibrosis.
  • RIP3 deficiency inhibited the TLR4-NF-κB pathway by suppressing ROCK1 in macrophages.
  • Overexpression of ROCK1 in macrophages exacerbated liver fibrosis in RIP3-deficient mice.

Conclusions:

  • RIP3 plays a critical pro-inflammatory role in liver fibrosis.
  • RIP3 regulates liver fibrosis through the ROCK1-TLR4-NF-κB signaling pathway in macrophages.
  • Targeting RIP3 in macrophages presents a potential therapeutic strategy for immune-mediated liver fibrosis.
Keywords:
BDLCCl4HFDinflammation

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