Hepatic macrophages in liver homeostasis and diseases-diversity, plasticity and therapeutic opportunities

Abstract

Macrophages, which are key cellular components of the liver, have emerged as essential players in the maintenance of hepatic homeostasis and in injury and repair processes in acute and chronic liver diseases. Upon liver injury, resident Kupffer cells (KCs) sense disturbances in homeostasis, interact with hepatic cell populations and release chemokines to recruit circulating leukocytes, including monocytes, which subsequently differentiate into monocyte-derived macrophages (MoMϕs) in the liver. Both KCs and MoMϕs contribute to both the progression and resolution of tissue inflammation and injury in various liver diseases. The diversity of hepatic macrophage subsets and their plasticity explain their different functional responses in distinct liver diseases. In this review, we highlight novel findings regarding the origins and functions of hepatic macrophages and discuss the potential of targeting macrophages as a therapeutic strategy for liver disease.

Keywords: Kupffer cells; liver cancer; liver fibrosis; liver inflammation; monocyte-derived macrophages.

Fig. 1

The role of hepatic macrophages in liver diseases. Schematic overview of the roles of Kupffer cells and monocyte-derived macrophages in liver disease. CCL C-C chemokine ligand, CTGF connective tissue growth factor, DAMP damage-associated molecular pattern, HGF hepatocyte growth factor, HSC hepatic stellate cell, IGF insulin-like growth factor, IL interleukin, MMP matrix metallopeptidase, MoMϕ monocyte-derived macrophages, PAMP pathogen-associated molecular pattern, PDGF platelet-derived growth factor, TGF transforming growth factor, TNF tumor necrosis factor, VEGF vascular endothelial growth factor

Fig. 2

Macrophage-based therapeutic approaches for liver disease. Schematic overview of the different therapeutic approaches that focus on the inflammatory system divided into those that hamper inflammatory cell recruitment, those that inhibit macrophage action, and those that shape macrophage function and polarization. ASK-1 apoptosis signal-regulating kinase 1, PPAR peroxisome proliferator-activated receptor, CCL C-C chemokine ligand, CCR C-C chemokine receptor