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Article Abstract
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 (e.g., 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-B 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-B) mice, the mechanism and functionality of Nogo-B macrophages were investigated in three murine liver fibrosis models, which were induced separately by bile duct ligation (BDL), methionine- and choline-deficient (MCD) diets, and carbon tetrachloride (CCl) 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 three liver fibrosis models. Importantly, Nogo-B deficiency inhibited NLRP3 inflammasome activation and necroptosis in macrophages both in vivo and in vitro. Notably, 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 USP14 restricted the degree of RIPK3 ubiquitination and increased RIPK3 stabilization.
Conclusion: 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.
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| http://dx.doi.org/10.1016/j.jcmgh.2025.101622 | DOI Listing |
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