Roles for Chemokines in Liver Disease Fabio Marra, Frank Tacke  Gastroenterology  Volume 147, Issue 3, Pages 577-594.e1 (September 2014) DOI: 10.1053/j.gastro.2014.06.043 Copyright © 2014 AGA Institute Terms and Conditions

Figure 1 Important chemokine pathways for the initiation of liver inflammation. Resident hepatic macrophages, Kupffer cells, are an important sensor of tissue injury. They become activated via pathogen-associated molecular patterns (PAMPs) from invading pathogens, by danger-associated molecular patterns (DAMPs) released from injured hepatocytes and cholangiocytes, and by stellate cells that also respond to danger signals. On activation, Kupffer cells release proinflammatory cytokines (TNF, IL-1) and chemokines (CXCL1, CXCL2, CXCL8, CXCL16, CCL2), which initiate the acute phase response, attract neutrophils (via CXCR1/CXCR2) that release cytotoxic and antimicrobial molecules (reactive oxygen species [ROS], oxidants, defensins), NKT cells (via CXCR6) that in turn perpetuate inflammatory responses via proinflammatory cytokines (TNF, IFN-γ), and inflammatory monocytes (via CCR2) that differentiate into proinflammatory hepatic macrophages. The figure represents a selection among the manifold immune cell subsets and chemokine pathways involved in the initiation of liver inflammation or injury. Gastroenterology 2014 147, 577-594.e1DOI: (10.1053/j.gastro.2014.06.043) Copyright © 2014 AGA Institute Terms and Conditions

Figure 2 (A) Chemokines in the pathogenesis of fatty liver and nonalcoholic steatohepatitis. In the AT, obesity leads to recruitment of monocytes from the bloodstream, predominantly via CCL2/CCR2. Within AT, macrophages undergo a phenotypic switch from an anti-inflammatory, M2 state to proinflammatory M1. CXC chemokines such as CXCL2 contribute to neutrophil recruitment, whereas others, including CCL20, increase the inflow of T lymphocytes. These changes result in AT insulin resistance, adipokine imbalance, and flow of lipotoxic free fatty acids (FFA) to the liver. These changes contribute to determine hepatic fatty degeneration, activation of Kupffer cells, which together with hepatocytes and stellate cells amplify inflammation via chemokines (CCL2 and CCL5), and recruitment of immune cells (eg, monocytes) into the liver. Chemokines have also been directly implicated in the accumulation of lipids within hepatocytes. (B) Chemokines in the pathogenesis of alcohol-related injury. Different CXC chemokines, particularly CXCL8, mediate recruitment of neutrophils, which contribute to tissue damage. CCL20, a ligand of CCR6, mediates inflammation and promotes fibrogenesis. In addition, CCL20 mediates the effects of LPS. CCL2 also contributes to inflammation, fibrosis, and possibly steatosis. Proinflammatory chemokines are mostly secreted by M1 macrophages, which may be counteracted and inhibited by M2-polarized cells. Gastroenterology 2014 147, 577-594.e1DOI: (10.1053/j.gastro.2014.06.043) Copyright © 2014 AGA Institute Terms and Conditions

Figure 3 Important chemokine pathways for the progression and regression of liver fibrosis. The scheme summarizes relevant chemokine-mediated actions of immune cell subset recruitment, interactions with parenchymal and nonparenchymal liver cells, and functionality in the context of progressing or regressing liver fibrosis, mainly based on experimental mouse models. Details are explained in the main text. Gastroenterology 2014 147, 577-594.e1DOI: (10.1053/j.gastro.2014.06.043) Copyright © 2014 AGA Institute Terms and Conditions

Figure 4 Chemokines and HCC. CXCL8 mediates recruitment of neutrophils, which favor invasion through secretion of matrix metalloproteinase 9 (MMP-9). In addition, CXCL8 regulates angiogenesis and the biology of tumor-initiating cells. CXCL8 and other CXC chemokines also directly stimulate growth of cancer cells. CXCL12 is involved in cancer growth and metastasis and contributes to the biology of tumor-initiating cells. CC chemokines regulate leukocyte trafficking, This includes CD8 T cells and NK cells, which exert antitumor effects, and regulatory T cells, which mediate immune evasion. Similarly, recruited tumor-associated macrophages may create an inflammatory antitumor environment or mediate immune suppression. Gastroenterology 2014 147, 577-594.e1DOI: (10.1053/j.gastro.2014.06.043) Copyright © 2014 AGA Institute Terms and Conditions

Supplementary Figure 1 Approaches to pharmacological interference with the chemokine system. (A) The interaction between a chemokine and a chemokine receptor is schematically shown. Modulation of chemokine signaling may be obtained by interfering with ligand binding with monoclonal antibodies (B) against the chemokine or (C) against the receptor. (D) Receptor antagonists prevent the occupation of the receptor by the ligand. (E) The abundance of the ligand may be reduced by the use of aptamers, such as oligonucleotides. (F) Small molecule inhibitors may prevent transmission of the signal downstream of the chemokine receptor. (G) Finally, truncated forms of chemokine ligands may work as receptor antagonists or partial agonists. Gastroenterology 2014 147, 577-594.e1DOI: (10.1053/j.gastro.2014.06.043) Copyright © 2014 AGA Institute Terms and Conditions