Fig. 4

Macrophages in chronic liver inflammation. Schematic overview of the roles of hepatic macrophage subsets in homeostasis and different chronic liver diseases. Homeostasis: Embryonically derived resident Kupffer cells (Res-KCs) reside within sinusoids, possess self-renewal capacity, and perform various functions, including phagocytosis of pathogens, regulation of lipid and iron metabolism [e.g., removal of red blood cells (RBCs)], clearance of cellular debris, and maintenance of immune tolerance. The following additional liver macrophage subsets derived from bone marrow (BM) monocytes are present: central vein macrophages (CV-Macs) and bile duct lipid-associated macrophages (BD-LAMs). The composition of the hepatic macrophage pool is altered during chronic inflammation. Cholestasis: Bile duct damage [e.g., primary sclerosing cholangitis (PSC)] triggers the release of chemoattractants (e.g., CCL2 and IL-18), leading to increased infiltration and periportal accumulation of monocyte-derived macrophages (mo-Macs). In this context, monocyte-derived KCs (Mo-KCs) exhibit potential for communication with HSCs via factors such as Gas6 and increased phagocytosis capacity. The presence of LAM-like macrophages has also been described. Alcohol: In alcohol-related liver disease (ALD), increased gut permeability results in increased bacterial translocation and entry of pathogen-associated molecular patterns (PAMPs) into the liver, e.g., lipopolysaccharide (LPS); persistent exposure to these PAMPs activates liver macrophages, causing TNF-α and reactive oxygen species (ROS) production and perpetuating liver injury. Experimental depletion of KCs in mice led to aberrant hepatocyte proliferation, mimicking human disease. MASLD/MASH: In metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), a reduction in Res-KC numbers occurs due to impaired self-renewal and overactivation by insults, e.g., free fatty acids (FFAs), that may trigger apoptosis. Furthermore, KCs undergo ferroptosis after hepdicin-induced increased iron uptake, which is stimulated by macrophage-derived NCF1, whereas hypoxia-induced factors such as HIF-2α can promote lysosomal cell death. Mo-Macs are recruited in response to hepatocyte-derived damage-associated molecular patterns (DAMPs) and chemokines released from activated KCs (e.g., CCL2, IL-1β, and TNF-α) and cholangiocytes (CCL2, CCL5, and CXCL1). LAMs of both KC and BM origin emerge and expand, expressing the TREM2, SPP1, and GPNMB markers. Fibrosis: Liver inflammation is perpetuated by activated KCs, some of which express TREM1, as well as by CCL2/CCR2-recruited monocytes and mo-Macs. KCs facilitate immune cell recruitment through the production of various chemokines (e.g., CCL9, CXLC2, and CXCL3) and promote HSC activation and differentiation via the production of profibrotic factors (e.g., PDGF and TGF-β). LAM-like Macs are also observed, along with profibrogenic TREM2⁺ CD9⁺ SPP1⁺ scar-associated macrophages (SAMs) and FABP5-expressing macrophages around the fibrotic niche. Syncytial macrophage structures have been shown to play a role in KC in mouse fibrosis models. Cancer: Tumor-associated macrophages (TAMs), monocytic myeloid-derived suppressor cells (M-MDSCs), and Res-KCs promote tumorigenesis and dampen immune responses in hepatocellular carcinoma (HCC). CD68⁺ CD11b⁺ CD16^- inflammatory macrophages (Inflammatory Macs) and CCR2⁺ S100A9⁺ TAMs accumulate periportally and around irregular blood vessels within tumors. In a hypoxic environment, the expression of matrix metalloproteinases (MMPs) and SPP1 denotes protumorigenic TAMs, which play roles in cancer stemness, epithelial‒mesenchymal transition (EMT) and neovascularization and dampen antitumor responses. PD-L1⁺ TAMs can have antitumour functions by facilitating the recruitment and activation of CXCR3⁺ effector memory T (T_EM) cells. Abbreviations: CCR chemokine receptor, CCL C-C motif chemokine ligand, CXCL C-X-C motif chemokine ligand, TLR toll-like receptor, LSECs liver sinusoidal endothelial cells. This figure was created with BioRender (biorender.com)