Department of Biomaterials Science and Technology, Faculty of Science and Technology, Technical Medical Center, University of Twente, Enschede, Netherlands.
Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, Aachen, Germany.
Front Immunol. 2019 Dec 3;10:2852. doi: 10.3389/fimmu.2019.02852. eCollection 2019.
Hepatic macrophages play a central role in maintaining homeostasis in the liver, as well as in the initiation and progression of liver diseases. Hepatic macrophages are mainly derived from resident hepatic macrophages called Kupffer cells or circulating bone marrow-derived monocytes. Kupffer cells are self-renewing and typically non-migrating macrophages in the liver and are stationed in the liver sinusoids in contrast to macrophages originating from circulating monocytes. Kupffer cells regulate liver homeostasis by mediating immunity against non-pathogenic blood-borne molecules, while participating in coordinated immune responses leading to pathogen clearance, leukocyte recruitment and antigen presentation to lymphocytes present in the vasculature. Monocyte-derived macrophages infiltrate into the liver tissue when metabolic or toxic damage instigates and are likely dispensable for replenishing the macrophage population in homeostasis. In recent years, different populations of hepatic macrophages have been identified with distinct phenotypes with discrete functions, far beyond the central dogma of M1 and M2 macrophages. Hepatic macrophages play a central role in the pathogenesis of acute and chronic liver failure, liver fibrosis, non-alcoholic fatty liver disease, alcoholic liver disease, viral hepatitis, and hepatocellular carcinoma, as well as in disease resolution. The understanding of the role of hepatic macrophages in liver diseases provides opportunities for the development of targeted therapeutics for respective malignancies. This review will summarize the current knowledge of the hepatic macrophages, their origin, functions, their critical role in maintaining homeostasis and in the progression or resolution of liver diseases. Furthermore, we will provide a comprehensive overview of the therapeutic targeting strategies against hepatic macrophages developed for the treatment of liver diseases.
肝脏巨噬细胞在维持肝脏内稳态以及肝脏疾病的发生和进展中发挥着核心作用。肝脏巨噬细胞主要来源于常驻于肝脏的巨噬细胞，称为库普弗细胞或循环骨髓源性单核细胞。库普弗细胞是自我更新的、通常是非迁移性的肝脏巨噬细胞，位于肝窦中，与来源于循环单核细胞的巨噬细胞不同。库普弗细胞通过介导对非致病性血源分子的免疫反应来调节肝脏内稳态，同时参与协调免疫反应，导致病原体清除、白细胞募集和抗原呈递给血管中的淋巴细胞。单核细胞衍生的巨噬细胞在代谢或毒性损伤引发时浸润到肝组织中，在维持内稳态时补充巨噬细胞群体可能是可有可无的。近年来，已经鉴定出不同表型的具有离散功能的肝脏巨噬细胞亚群，远远超出了 M1 和 M2 巨噬细胞的中心教条。肝脏巨噬细胞在急性和慢性肝功能衰竭、肝纤维化、非酒精性脂肪性肝病、酒精性肝病、病毒性肝炎和肝细胞癌以及疾病缓解中发挥着核心作用。了解肝脏巨噬细胞在肝脏疾病中的作用为开发针对各自恶性肿瘤的靶向治疗提供了机会。这篇综述将总结肝脏巨噬细胞的当前知识，包括它们的起源、功能、在维持内稳态以及在肝脏疾病的进展或缓解中的关键作用。此外，我们将全面概述为治疗肝脏疾病而开发的针对肝脏巨噬细胞的治疗靶向策略。
