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Updated: Sep 9, 2025
Isolation, Characterization, and Purification of Macrophages from Tissues Affected by Obesity-related Inflammation
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.
Background & Aims:
Liver fibrosis is characterized by sustained injury stress, chronic inflammation, and repeated cell death and repair, all of which promote the progression of end-stage liver diseases (eg, liver cirrhosis and carcinoma). As an endoplasmic reticulum-residential protein, Nogo-B strongly regulates macrophage function, but whether Nogo-B-decorated macrophages affect inflammation and progression during liver fibrosis is unclear. The purpose of our current study was to elucidate the roles of Nogo-Bhigh macrophages during liver fibrosis development.
Methods:
The expression and distribution of Nogo-B were analyzed in clinical specimens and animal models. By utilizing myeloid-specific Nogo-B knockout (Nogo-Bmko) mice, the mechanism and functionality of Nogo-Bhigh macrophages were investigated in 3 murine liver fibrosis models, which were induced separately by bile duct ligation, methionine- and choline-deficient diets, and carbon tetrachloride administration.
Results:
Our study revealed the predominant expression of Nogo-B in fibrotic liver macrophages and its positive correlation with fibrosis stage. Myeloid-specific Nogo-B deficiency effectively alleviated liver inflammation, injury, and fibrosis in 3 liver fibrosis models. Importantly, Nogo-B deficiency inhibited NOD-like receptor protein 3 (NLRP3) inflammasome activation and necroptosis in macrophages both in vivo and in vitro. Notably, receptor-interacting serine-threonine kinase 3 (RIPK3) is vital for Nogo-B-driven NLRP3 inflammasome activation and necroptosis in macrophages. Additionally, adoptive transfer of macrophages revealed that the Nogo-B/RIPK3 axis promoted NLRP3 inflammasome activation and necroptosis and accelerated liver fibrosis. Mechanistically, Nogo-B-mediated recruitment of ubiquitin-specific protease 14 restricted the degree of RIPK3 ubiquitination and increased RIPK3 stabilization.
Conclusions:
Nogo-B facilitates liver fibrosis by recruiting the deubiquitination enzyme USP14, which increases the stabilization of RIPK3 and promotes NLRP3 inflammasome activation and necroptosis in macrophages.
