Department and Institute of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Int Immunopharmacol. 2023 Apr;117:109631. doi: 10.1016/j.intimp.2022.109631. Epub 2023 Mar 4.
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.
纤维蛋白原样蛋白 2（Fgl2）在受到感染或炎性细胞因子刺激时能强烈激活巨噬细胞，并且在丙型肝炎病毒（HCV）感染的肝硬化患者的肝组织中显著增加。然而，Fgl2 参与肝纤维化发病机制中巨噬细胞功能的分子机制尚不清楚。在这项研究中，我们证明了乙型肝炎病毒（HBV）感染患者和实验模型中肝内 Fgl2 表达增加与肝炎症和高级别肝纤维化有关。Fgl2 的基因缺失减轻了肝炎症和纤维化进展。Fgl2 促进 M1 巨噬细胞极化，并增加促炎细胞因子的产生，从而促进炎症损伤和纤维化的发展。此外，Fgl2 增加了线粒体活性氧（ROS）的产生并调节了线粒体功能。Fgl2 介导的 mtROS 参与了巨噬细胞的激活和极化。我们进一步证明，在巨噬细胞中，Fgl2 不仅定位于细胞质，还定位于线粒体，在那里它与细胞质和线粒体热休克蛋白 90（HSP90）结合。在机制上，Fgl2 与 HSP90 相互作用，阻碍 HSP90 与其靶蛋白 Akt 的相互作用，显著抑制 Akt 磷酸化和下游 FoxO1 磷酸化。这些结果揭示了 Fgl2 对 M1 极化巨噬细胞中炎症损伤和线粒体功能障碍的不同调控层。因此，Fgl2 可能是肝纤维化治疗的一个有效靶点。
