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Review
. 2019 Dec 3;10:2852.
doi: 10.3389/fimmu.2019.02852. eCollection 2019.

Therapeutic Targeting of Hepatic Macrophages for the Treatment of Liver Diseases

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Free PMC article
Review

Therapeutic Targeting of Hepatic Macrophages for the Treatment of Liver Diseases

Daphne van der Heide et al. Front Immunol. .
Free PMC article

Abstract

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.

Keywords: Kupffer cells; hepatic macrophages; liver diseases; monocytes; targeted therapeutics.

Figures

Figure 1
Figure 1
Origin of hepatic macrophages. The figure depicts the diverse origin of hepatic macrophages. Hepatic macrophages can arise from bone marrow derived monocytes, spleen derived monocytes and peritoneum-derived macrophages. Resident hepatic macrophages (Kupffer cells, KCs) develop in three waves at multiple anatomical locations. In the first wave (primitive hematopoiesis), primitive erythroid progenitors originate and differentiate into primitive erythroblasts in the yolk sac. In the second wave (transient hematopoiesis), erythro-myeloid progenitors develop in the yolk sac and migrate into the nascent fetal liver. In the third wave (definitive hematopoiesis), hematopoietic stem cells arise intra-embryonically from hemogenic endothelium in the aorta-gonad-mesonephros region and in the umbilical and vitelline arteries. Hematopoietic stem cells migrate into the fetal liver and expand/differentiate into resident KCs. Hepatic macrophages mediate different functions in organ homeostasis, impairment, restoration, and in fibrosis. APC, antigen presenting cells; CCL, chemokine (C-C) motif ligand; CCR, chemokine (C-C) motif receptor; CD, cluster of differentiation; Clec4f, C-type lectin domain family 4 member F; CX3CR1, C-X3-C motif chemokine receptor 1; ECM, extracellular matrix; F4/80, EGF-like module-containing mucin-like hormone receptor-like 1; GATA6, GATA-binding factor 6; IL, interleukin; MIP-1, macrophage inflammatory protein 1; Tim4, T-cell membrane protein 4; TGFβ, transforming growth factor beta; TNF-α, tumor necrosis factor-α; Treg, regulatory T cells; Ly-6C, lymphocyte antigen 6 complex locus C1.
Figure 2
Figure 2
Macrophages in hepatic disease. Hepatic macrophages, KCs and MoMFs, are the key players in various types of liver disease including acute liver failure (ALF), liver fibrosis, non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), viral hepatitis and hepatocellular carcinoma (HCC). They modulate adaptive immune responses, fibrosis progression/resolution, sense disease severity, contribute to the establishment of a tumorigenic environment, promote tumor growth, angiogenesis, invasion, and metastasis. CCL, chemokine (C-C) motif ligand; EGF, epidermal growth factor; HCC, hepatocellular carcinoma; IL, interleukin; IFN-γ, interferon-γ; KCs, Kupffer cells; LPS, lipopolysaccharides; Ly-6C, lymphocyte antigen 6 complex locus C1; MCP-1, monocyte chemoattractant protein 1; MMPs, matrix metalloproteinases; MoMFs, monocyte derived macrophages; mtDNA, mitochondrial DNA; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; NAMs, NASH-associated macrophages; PD-L, programmed death-ligand; PDGF, platelet-derived growth factor; ROS, reactive oxygen species; TAMs, tumor-associated macrophages; TGFβ, transforming growth factor beta; TNF-α, tumor necrosis factor-α; VEGF, vascular endothelial growth factor.
Figure 3
Figure 3
Therapeutic targeting of hepatic macrophages. Modulation of macrophage polarization and function, inhibition of Kupffer cell activation, and dampening of monocyte recruitment into the inflamed liver are the three strategies that have been investigated for the resolution of hepatic inflammation and fibrogenesis. ASK1, Apoptosis signal-regulating kinase 1; CCL, chemokine (C-C) motif ligand; CCR, chemokine (C-C) motif receptor; CSF-1R, colony stimulating factor 1 receptor; DAMP, damage-associated molecular patterns; HMGB1, High mobility group box 1 protein; mNOX-E36, emapticap pegol; MTC, Mannose-modified trimethyl chitosan-cysteine; NASH, non-alcoholic steatohepatitis; NP, nanoparticle; PLGA, poly(lactic-co-glycolic acid); PRR, pattern recognition receptors; TLR, Toll like receptors.

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