Fibrinogen-like protein 2 (Fgl2) robustly activates macrophages in response to infection or inflammatory cytokine challenge and is markedly increased in the liver tissues of liver cirrhosis patientswithhepatitisCvirus(HCV) infection. However, the molecular mechanism underlying the involvement of Fgl2 in macrophage function in the pathogenesis of liver fibrosis remains unclear. In this study, we demonstrated that increased hepatic Fgl2 expression was associated with hepatic inflammation and high-grade liver fibrosis in patients with hepatitis B virus (HBV) infection and experimental models. Genetic ablation of Fgl2 alleviated hepatic inflammation and fibrosis progression. Fgl2 promoted M1 macrophage polarization and increased the production of proinflammatory cytokines that contribute to inflammatory damage and fibrosis development. In addition, Fgl2 augmented mitochondrial reactive oxygen species (ROS) production and modulated mitochondrial functions. Fgl2-mediated mtROS were involved in macrophage activation and polarization. We further demonstrated that in macrophages, Fgl2 localized to not only the cytosol but also mitochondria, where it bound to cytosolic and mitochondrial heat shock protein 90 (HSP90). Mechanistically, Fgl2 interacted with HSP90, hindering the interaction of HSP90 with its target protein Akt, significantly inhibiting Akt phosphorylation and downstream FoxO1 phosphorylation. These results reveal different layers of regulation of Fgl2 that are necessary for inflammatory damage and mitochondrial dysfunction in M1-polarized macrophages. Therefore, Fgl2 may be a potent target in liver fibrosis treatment.
Keywords: Fibrinogen-like protein 2; Liver fibrosis; Macrophage polarization; Mitochondrial dysfunction; Mitochondrial reactive oxygen species.
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