利用肝巨噬细胞代谢促进肝脏再生

Promoting Liver Regeneration by Utilizing Liver Macrophage Metabolism

肝脏再生是一个动态和调节的过程,涉及炎症、肉芽和组织重塑。肝巨噬细胞大量分布在肝脏中,是积极参与每一步协调肝脏再生的重要成分。在稳态肝脏中,常驻巨噬细胞(库普弗细胞)获得耐受表型并有助于免疫耐受。在毒性诱导的损伤或物理切除后,库普弗细胞以及单核细胞衍生的巨噬细胞可以被激活并促进炎症过程,该炎症过程支持肝肌成纤维细胞的存活和激活,从而促进瘢痕组织的形成。随后,这些巨噬细胞在分解阶段表现出对细胞外基质重塑至关重要的抗炎作用。然而,持续损伤诱导的慢性炎症通常会导致肝巨噬细胞功能障碍,从而加剧肝细胞损伤,并引发进一步的肝纤维化甚至肝硬化。新兴的巨噬细胞靶向策略已在临床前和临床研究中显示出疗效。越来越多的证据表明,代谢重组为表观遗传学修饰提供了底物,赋予单核细胞/巨噬细胞延长的“先天免疫记忆”。因此,有理由构思代谢重编程巨噬细胞的新治疗策略,从而介导肝脏炎症管理和肝脏再生的稳态或修复过程。

Liver regeneration is a dynamic and regulated process involving inflammation, granulation and tissue remodeling. A large number of liver macrophages are distributed in the liver and are im-portant components that actively participate in the coordination of liver regeneration at every step. In the homeostatic liver, resident macrophages (Kupfer cells) acquire a tolerance phenotype and contribute to immune tolerance. Following toxic-induced injury or physical excision, Kupfer cells, as well as monocyte-derived macrophages, can be activated and promote the inflammatory process that supports the survival and activation of hepatic myoblasts, thereby promoting scar tissue for-mation. Subsequently, these macrophages exhibit anti-inflammatory effects critical for extracellular matrix remodeling during the decomposition phase. However, chronic inflammation induced by sustained injury often leads to dysfunction of liver macrophages, which worsens liver cell damage and triggers further liver fibrosis and even cirrhosis. Emerging macrophage targeting strategies have shown efficacy in preclinical and clinical studies. There is growing evidence that metabolic re-combination provides a substrate for epigenetic modifications that confer extended “innate im-mune memory” on monocytes/macrophages. Therefore, it is reasonable to conceive of novel thera-peutic strategies for metabolically reprogramming macrophages, thereby mediating homeostasis or repair processes in liver inflammation management and liver regeneration.