Hepatic macrophages in homeostasis and liver diseases: from pathogenesis to novel therapeutic strategies

Abstract

Macrophages represent a major cell type of innate immunity and have emerged as a critical player and therapeutic target in many chronic inflammatory diseases. Hepatic macrophages consist of Kupffer cells, which are originated from the fetal yolk-sack, and infiltrated bone marrow-derived monocytes/macrophages. Hepatic macrophages play a central role in maintaining homeostasis of the liver and in the pathogenesis of liver injury, making them an attractive therapeutic target for liver diseases. However, the various populations of hepatic macrophages display different phenotypes and exert distinct functions. Thus, more research is required to better understand these cells to guide the development of macrophage-based therapeutic interventions. This review article will summarize the current knowledge on the origins and composition of hepatic macrophages, their functions in maintaining hepatic homeostasis, and their involvement in both promoting and resolving liver inflammation, injury, and fibrosis. Finally, the current strategies being developed to target hepatic macrophages for the treatment of liver diseases will be reviewed.

Figure 1

Involvement of hepatic macrophage populations during the initiation, progression and resolution of liver injury in mouse models. In the initial phase, hepatocyte damage triggers the release of damage-associated molecular pattern molecules (DAMPs) which stimulate Kupffer cell (KC) activation activation. Endotoxin from the gut–liver axis may additionally endorse Kupffer cell activation. Activated Kupffer cells secrete pro-inflammatory cytokines, including IL-1β and TNFα, which contribute to hepatocyte injury. Hepatocytes, stellate cells and Kupffer cells secrete chemokines such as CCL2 that promotes the recruitment of Ly-6C^hi monocytes into the liver, where they develop into Ly-6C⁺ macrophages. These cells promote the progression of liver injury by secreting pro-inflammatory cytokines and producing ROS. During chronic injury, Ly-6C⁺ macrophages also trigger HSC activation and promote myofibroblast production of extracellular matrix through releasing pro-fibrotic mediators, such as tumor growth factor (TGF)-β, connective tissue growth factor (CTGF), PDGF, and tissue inhibitor of matrix metalloproteinase (TIMPs). Phagocytosis of dead cells initiates the resolution of inflammation and tissue restoration. Upon phagocytosis or other resolution stimuli, the Ly-6C^hi macrophages switch to Ly-6C^low macrophages that exhibit a restorative phenotype. The Ly-6C^low macrophages, as well as Kupffer cells produce anti-inflammatory mediators, such as IL-1 receptor antagonist (IL-1Ra) and IL-10. They release growth factors, including hepatocyte growth factor (HGF) and VEGF. Moreover, the Ly-6C^low macrophages produce matrix metalloproteinases (MMP-9, -12, -13) and promote the degradation of excessive extracellular matrix proteins. Overall, the phenotype and functional heterogeneity of hepatic macrophages play critical roles in determining the balance between the mechanisms of progression and resolution of tissue injury during both acute and chronic liver injuries.