Macrophage Nogo-B drives liver fibrosis

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-Bhigh macrophages during liver fibrosis development. 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 three murine liver fibrosis models, which were induced separately by bile duct ligation (BDL), methionine- and choline-deficient (MCD) diets, and carbon tetrachloride (CCl4) administration. 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. 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.