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Updated: Sep 9, 2025
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Published on: April 3, 2017
Macrophage Nogo-B Drives Liver Fibrosis.
Lei Zhang1, Ming Ni2, Jiahao Si2
1Hepatobiliary Center, the First Affiliated Hospital with Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences; Nanjing, Jiangsu Province, China; Research Center of Surgery, BenQ Medical Center, the Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, China.
Nogo-B protein in liver macrophages drives fibrosis by promoting inflammation and cell death. Inhibiting Nogo-B alleviates liver fibrosis, offering a potential therapeutic target for liver diseases.
Area of Science:
- Immunology
- Hepatology
- Cellular Biology
Background:
- Liver fibrosis, a precursor to cirrhosis and carcinoma, involves chronic inflammation and cell death.
- Nogo-B, an endoplasmic reticulum protein, influences macrophage function, but its role in liver fibrosis is unknown.
- Understanding Nogo-B's role in macrophages is crucial for deciphering liver fibrosis progression.
Purpose of the Study:
- To investigate the role of Nogo-B-expressing macrophages in liver fibrosis development.
- To elucidate the underlying molecular mechanisms of Nogo-B in promoting liver inflammation and fibrosis.
Main Methods:
- Analyzed Nogo-B expression in clinical liver fibrosis specimens and animal models.
- Utilized myeloid-specific Nogo-B knockout (Nogo-Bmko) mice in three distinct liver fibrosis models (BDL, MCD diet, CCl4).
- Investigated macrophage activation, NLRP3 inflammasome, and necroptosis pathways in vitro and in vivo.
- Performed adoptive transfer of macrophages to assess Nogo-B's functional impact.
Main Results:
- Nogo-B expression is elevated in fibrotic liver macrophages and correlates with fibrosis severity.
- Myeloid-specific Nogo-B deficiency significantly reduced liver inflammation, injury, and fibrosis.
- Nogo-B deficiency suppressed NLRP3 inflammasome activation and necroptosis in macrophages.
- The Nogo-B/RIPK3 axis was identified as critical for NLRP3 inflammasome activation and necroptosis.
- Nogo-B promotes RIPK3 stabilization by recruiting USP14, a deubiquitination enzyme.
Conclusions:
- Nogo-B plays a critical role in promoting liver fibrosis by enhancing macrophage-mediated inflammation and necroptosis.
- The Nogo-B/USP14/RIPK3 axis is a key pathway driving liver fibrosis progression.
- Targeting Nogo-B may offer a novel therapeutic strategy for treating liver fibrosis and related end-stage liver diseases.
