Introduction: Liver fibrosis is characterized by sustained injury stress and chronic inflammation, repeated cell death and repair, all of which promote the progression of end-stage liver diseases (e.g. liver cirrhosis, carcinoma). As an endoplasmic reticulum-residential protein, Nogo-B possesses strong regulation abilities on macrophage function, but whether Nogo-B-decorated macrophage affects inflammation and progression is unclear during liver fibrosis. Herein, our aim is to elucidate the roles of Nogo-Bhigh macrophage during the liver fibrosis development.
Method: Expression and distribution of Nogo-B were analyzed with clinical specimens and animal models. Utilizing myeloid-specific Nogo-B knockout (Nogo-Bmko) mice, the mechanism and functionality of Nogo-Bhigh macrophage were investigated in three murine liver fibrosis models, which were  induced separately by the bile duct ligation (BDL), the methionine- and choline-deficient (MCD) diet, and the carbon tetrachloride (CCl4) administration.
Results: Our study found predominant expression of Nogo-B in fibrotic liver macrophages and their positive correlation with fibrotic stages. Myeloid-specifific Nogo-B deficiency effectively alleviated liver inflammation, injury and fibrosis in three animal models. Importantly, Nogo-B deficiency inhibited NLRP3 inflammasome activation and necroptosis of macrophages in vivo and in vitro. Notably, RIPK3 was vital for Nogo-B driving NLRP3 inflammasome activation and necroptosis of macrophages. Additionally, adoptive transfer of macrophages indicated Nogo-B/RIPK3 axis promoted NLRP3 inflammasome activation and necroptosis, and accelerated liver fibrosis. Mechanistically, Nogo-B recruited USP14 restricted the ubiquitination degration of RIPK3 and enhanced RIPK3 stabilization.
Conclusions: Nogo-B facilitates liver fibrosis, by recruiting deubiquitination enzyme USP14, which increases stabilization of RIPK3 and promotes NLRP3 inflammasome activation and necroptosis in macrophages.