Inflammation is a major contributor to the pathogenesis of almost all liver diseases. Low-molecular-weight proteins called chemokines are the main drivers of liver infiltration by immune cells such as macrophages, neutrophils and others during an inflammatory response. During the past 25 years, tremendous progress has been made in understanding the regulation and functions of chemokines in the liver. This Review summarizes three main aspects of the latest advances in the study of chemokine function in liver diseases. First, we provide an overview of chemokine biology, with a particular focus on the genetic and epigenetic regulation of chemokine transcription as well as on the cell type-specific production of chemokines by liver cells and liver-associated immune cells. Second, we highlight the functional roles of chemokines in liver homeostasis and their involvement in progression to disease in both human and animal models. Third, we discuss the therapeutic opportunities targeting chemokine production and signalling in the treatment of liver diseases, such as alcohol-associated liver disease and nonalcoholic steatohepatitis, including the relevant preclinical studies and ongoing clinical trials.
Chemokines are secreted mediators that regulate the infiltration of immune cells into the liver and modulate the activation and proliferation of almost all liver cell types.
Individual chemokines can interact with their corresponding receptors based on their structural characteristics and local context and can contribute to liver homeostasis by interacting with immune and non-immune liver cells.
Tumour necrosis factor (TNF), IL-6 and many other cytokines can rapidly stimulate the transcription of pro-inflammatory chemokines in a robust and co-regulated manner through the epigenetically primed chromatin 3D conformation of enhancer–promoter interactions.
Chemokines are associated with liver disease and it is critical to identify different major players that provide the similarities and dissimilarities between mouse and human genomic arrangement.
Current drug development based on chemokines and receptors in liver diseases is limited and can be greatly improved with novel therapeutic strategies.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Deuel, T. F., Keim, P. S., Farmer, M. & Heinrikson, R. L. Amino acid sequence of human platelet factor 4. Proc. Natl Acad. Sci. USA 74, 2256–2258 (1977).
Anisowicz, A., Bardwell, L. & Sager, R. Constitutive overexpression of a growth-regulated gene in transformed Chinese hamster and human cells. Proc. Natl Acad. Sci. USA 84, 7188–7192 (1987).
Sugano, S., Stoeckle, M. Y. & Hanafusa, H. Transformation by Rous sarcoma virus induces a novel gene with homology to a mitogenic platelet protein. Cell 49, 321–328 (1987).
Vinader, V. & Afarinkia, K. A beginner’s guide to chemokines. Future Med. Chem. 4, 845–852 (2012).
Chang, B. et al. Short- or long-term high-fat diet feeding plus acute ethanol binge synergistically induce acute liver injury in mice: an important role for CXCL1. Hepatology 62, 1070–1085 (2015).
Marra, F. & Tacke, F. Roles for chemokines in liver disease. Gastroenterology 147, 577–594.e1 (2014).
Hughes, C. E. & Nibbs, R. J. B. A guide to chemokines and their receptors. FEBS J. 285, 2944–2971 (2018).
Rot, A. Chemokine patterning by glycosaminoglycans and interceptors. Front. Biosci. 15, 645–660 (2010).
Joseph, P. R. B. et al. Lysines and arginines play non-redundant roles in mediating chemokine-glycosaminoglycan interactions. Sci. Rep. 8, 12289 (2018).
Luster, A. D. Chemokines–chemotactic cytokines that mediate inflammation. N. Engl. J. Med. 338, 436–445 (1998). This is one of the early reviews that introduced the burgeoning family of cytokines, with special emphasis on their role in the pathophysiology of disease and their potential as targets for therapy.
Charo, I. F. & Ransohoff, R. M. The many roles of chemokines and chemokine receptors in inflammation. N. Engl. J. Med. 354, 610–621 (2006).
Laing, K. J. & Secombes, C. J. Trout CC chemokines: comparison of their sequences and expression patterns. Mol. Immunol. 41, 793–808 (2004).
Raman, D., Sobolik-Delmaire, T. & Richmond, A. Chemokines in health and disease. Exp. Cell Res. 317, 575–589 (2011).
Sahin, H., Trautwein, C. & Wasmuth, H. E. Functional role of chemokines in liver disease models. Nat. Rev. Gastroenterol. Hepatol. 7, 682–690 (2010). This paper summarized the chemokines in experimental liver disease models, the advances that might lead to preclinical applications and the roles of chemokine receptors as promising pharmacologically targetable molecules.
Gollomp, K. et al. Neutrophil accumulation and NET release contribute to thrombosis in HIT. JCI Insight 3, e99445 (2018).
Neumann, K. et al. Chemokine transfer by liver sinusoidal endothelial cells contributes to the recruitment of CD4+ T cells into the murine liver. PLoS ONE 10, e0123867 (2015).
Yano, T., Ohira, M., Nakano, R., Tanaka, Y. & Ohdan, H. Hepatectomy leads to loss of TRAIL-expressing liver NK cells via downregulation of the CXCL9-CXCR3 axis in mice. PLoS ONE 12, e0186997 (2017).
Ambade, A. et al. Pharmacological inhibition of CCR2/5 signaling prevents and reverses alcohol-induced liver damage, steatosis, and inflammation in mice. Hepatology 69, 1105–1121 (2019).
Krenkel, O. et al. Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis. Hepatology 67, 1270–1283 (2018).
Gavegnano, C., Savarino, A., Owanikoko, T. & Marconi, V. C. Crossroads of cancer and HIV-1: pathways to a cure for HIV. Front. Immunol. 10, 2267 (2019).
Deng, H. et al. Identification of a major co-receptor for primary isolates of HIV-1. Nature 381, 661–666 (1996).
Dragic, T. et al. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature 381, 667–673 (1996).
Oberlin, E. et al. The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature 382, 833–835 (1996).
Bleul, C. C. et al. The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry. Nature 382, 829–833 (1996).
Pola, R. et al. Monocyte chemoattractant protein-1 (MCP-1) gene polymorphism and risk of Alzheimer’s disease in Italians. Exp. Gerontol. 39, 1249–1252 (2004).
Pham, M. H. et al. The rs1024611 regulatory region polymorphism is associated with CCL2 allelic expression imbalance. PLoS ONE 7, e49498 (2012).
Mascheretti, S. et al. Genetic variants in the CCR gene cluster and spontaneous viral elimination in hepatitis C-infected patients. Clin. Exp. Immunol. 136, 328–333 (2004).
Pineda-Tenor, D. et al. Single nucleotide polymorphisms of CXCL9-11 chemokines are associated with liver fibrosis in HIV/HCV-coinfected patients. J. Acquir. Immune Defic. Syndr. 68, 386–395 (2015).
Hsu, S. H. & Ghoshal, K. MicroRNAs in liver health and disease. Curr. Pathobiol. Rep. 1, 53–62 (2013).
Saiman, Y. & Friedman, S. L. The role of chemokines in acute liver injury. Front. Physiol. 3, 213 (2012).
Gao, B., Ahmad, M. F., Nagy, L. E. & Tsukamoto, H. Inflammatory pathways in alcoholic steatohepatitis. J. Hepatol. 70, 249–259 (2019). An important review about the roles of multiple cell types that are involved in inflammation in alcoholic steatohepatitis, including resident macrophages and infiltrating monocytes, as well as other cell types in the innate and adaptive immune system.
Brown, J. D. et al. NF-κB directs dynamic super enhancer formation in inflammation and atherogenesis. Mol. Cell 56, 219–231 (2014). This is one of the early studies about how BET bromodomain inhibition abrogates super-enhancer-mediated inflammatory transcription, atherogenic endothelial responses and atherosclerosis both in vitro and in vivo.
Ohmori, Y., Schreiber, R. D. & Hamilton, T. A. Synergy between interferon-gamma and tumor necrosis factor-alpha in transcriptional activation is mediated by cooperation between signal transducer and activator of transcription 1 and nuclear factor kappaB. J. Biol. Chem. 272, 14899–14907 (1997).
Li, Q. J. et al. MAP kinase phosphorylation-dependent activation of Elk-1 leads to activation of the co-activator p300. EMBO J. 22, 281–291 (2003).
Sanyal, A., Lajoie, B. R., Jain, G. & Dekker, J. The long-range interaction landscape of gene promoters. Nature 489, 109–113 (2012).
Carey, M. The enhanceosome and transcriptional synergy. Cell 92, 5–8 (1998).
Bulger, M. & Groudine, M. Functional and mechanistic diversity of distal transcription enhancers. Cell 144, 327–339 (2011).
Heinz, S., Romanoski, C. E., Benner, C. & Glass, C. K. The selection and function of cell type-specific enhancers. Nat. Rev. Mol. Cell Biol. 16, 144–154 (2015). Enhancers are genetic elements that have major roles in determining cell type-specific gene expression patterns and responses to internal and external signals. An understanding of the mechanisms underlying the cell type-specific selection and function of enhancers will improve our understanding of the effects of natural genetic variation on complex phenotypes and diseases.
Hnisz, D. et al. Super-enhancers in the control of cell identity and disease. Cell 155, 934–947 (2013).
Dekker, J. et al. The 4D nucleome project. Nature 549, 219–226 (2017).
Jin, F. et al. A high-resolution map of the three-dimensional chromatin interactome in human cells. Nature 503, 290–294 (2013). This is one of the important studies about the use of 3C-based techniques to cover a whole-genome, unbiased view of chromatin interactions, including the characterization on the dynamics of promoter–enhancer contacts after TNF signalling in cells.
Barnes, P. J. & Karin, M. Nuclear factor-κB: a pivotal transcription factor in chronic inflammatory diseases. N. Engl. J. Med. 336, 1066–1071 (1997).
Higashijima, Y. et al. Coordinated demethylation of H3K9 and H3K27 is required for rapid inflammatory responses of endothelial cells. EMBO J. 39, e103949 (2020).
Fanucchi, S. et al. Immune genes are primed for robust transcription by proximal long noncoding RNAs located in nuclear compartments. Nat. Genet. 51, 138–150 (2019). This study shows that 3D chromatin topology enables CXCL family genes to engage in chromosomal contacts with a subset of long non-coding RNAs under a powerful enhancer.
Tarjan, D. R., Flavahan, W. A. & Bernstein, B. E. Epigenome editing strategies for the functional annotation of CTCF insulators. Nat. Commun. 10, 4258 (2019).
Dominguez, M. et al. Hepatic expression of CXC chemokines predicts portal hypertension and survival in patients with alcoholic hepatitis. Gastroenterology 136, 1639–1650 (2009). A prospective study about hepatic expression of the CXC subfamily of chemokines, including CXCL1 and CXCL8, with histological findings to correlate with the prognosis of patients with alcoholic hepatitis.
Liu, M. et al. Cytokine induced inflammatory chemokine production is under super enhancer regulation in alcoholic hepatitis hepatology. Hepatology 70, 186A–187A (2019).
The FANTOM Consortium and the RIKEN PMI and CLST (DGT). A promoter-level mammalian expression atlas. Nature 507, 462–470 (2014).
van de Werken, H. J. et al. 4C technology: protocols and data analysis. Methods Enzymol. 513, 89–112 (2012).
Nicodeme, E. et al. Suppression of inflammation by a synthetic histone mimic. Nature 468, 1119–1123 (2010).
Fok, E. T., Davignon, L., Fanucchi, S. & Mhlanga, M. M. The lncRNA connection between cellular metabolism and epigenetics in trained immunity. Front. Immunol. 9, 3184 (2018).
Kubes, P. & Jenne, C. Immune responses in the liver. Annu. Rev. Immunol. 36, 247–277 (2018).
Oo, Y. H., Shetty, S. & Adams, D. H. The role of chemokines in the recruitment of lymphocytes to the liver. Dig. Dis. 28, 31–44 (2010).
Zlotnik, A., Yoshie, O. & Nomiyama, H. The chemokine and chemokine receptor superfamilies and their molecular evolution. Genome Biol. 7, 243 (2006).
Wasmuth, H. E. et al. Antifibrotic effects of CXCL9 and its receptor CXCR3 in livers of mice and humans. Gastroenterology 137, 309–319 319.e1-3 (2009).
Sahin, H. et al. Chemokine Cxcl9 attenuates liver fibrosis-associated angiogenesis in mice. Hepatology 55, 1610–1619 (2012).
Shiraha, H., Glading, A., Gupta, K. & Wells, A. IP-10 inhibits epidermal growth factor-induced motility by decreasing epidermal growth factor receptor-mediated calpain activity. J. Cell Biol. 146, 243–254 (1999).
Zimmermann, H. W. & Tacke, F. Modification of chemokine pathways and immune cell infiltration as a novel therapeutic approach in liver inflammation and fibrosis. Inflamm. Allergy Drug Targets 10, 509–536 (2011).
Bigorgne, A. E. et al. TLR4-dependent secretion by hepatic stellate cells of the neutrophil-chemoattractant CXCL1 mediates liver response to gut microbiota. PLoS ONE 11, e0151063 (2016).
Aguilar-Bravo, B. et al. Ductular reaction cells display an inflammatory profile and recruit neutrophils in alcoholic hepatitis. Hepatology 69, 2180–2195 (2019).
Roh, Y. S., Zhang, B., Loomba, R. & Seki, E. TLR2 and TLR9 contribute to alcohol-mediated liver injury through induction of CXCL1 and neutrophil infiltration. Am. J. Physiol. Gastrointest. Liver Physiol. 309, G30–G41 (2015).
Robinson, M. W., Harmon, C. & O’Farrelly, C. Liver immunology and its role in inflammation and homeostasis. Cell. Mol. Immunol. 13, 267–276 (2016).
Sahin, H., Berres, M. L. & Wasmuth, H. E. Therapeutic potential of chemokine receptor antagonists for liver disease. Expert Rev. Clin. Pharmacol. 4, 503–513 (2011).
Kanamori-Katayama, M. et al. Unamplified cap analysis of gene expression on a single-molecule sequencer. Genome Res. 21, 1150–1159 (2011).
Krausgruber, T. et al. Structural cells are key regulators of organ-specific immune responses. Nature 583, 296–302 (2020). This in vivo bulk RNA-seq study shows that, within 2 hours of TNF treatment in mice, liver endothelial cells are the only structural cell type in liver to have a significant CXCL1 mRNA level increase compared with other cell types such as hepatocytes and fibroblasts.
Girbl, T. et al. Distinct compartmentalization of the chemokines CXCL1 and CXCL2 and the atypical receptor ACKR1 determine discrete stages of neutrophil diapedesis. Immunity 49, 1062–1076.e6 (2018).
MacParland, S. A. et al. Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations. Nat. Commun. 9, 4383 (2018).
Tabula Muris, C. et al. Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris. Nature 562, 367–372 (2018). An early paper on mouse single-cell transcriptomic data comprising >100,000 cells from 20 organs and tissues.
GBD 2017 Cirrhosis Collaborators. The global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol. Hepatol. 5, 245–266 (2020).
Colombo, M. et al. Hepatocellular carcinoma in Italian patients with cirrhosis. N. Engl. J. Med. 325, 675–680 (1991).
El–Serag, H. B. & Rudolph, K. L. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132, 2557–2576 (2007).
Guicciardi, M. E. et al. Macrophages contribute to the pathogenesis of sclerosing cholangitis in mice. J. Hepatol. 69, 676–686 (2018).
Tacke, F. Targeting hepatic macrophages to treat liver diseases. J. Hepatol. 66, 1300–1312 (2017).
Lefebvre, E. et al. Antifibrotic effects of the dual CCR2/CCR5 antagonist cenicriviroc in animal models of liver and kidney fibrosis. PLoS ONE 11, e0158156 (2016).
Ramachandran, P. et al. Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis. Proc. Natl Acad. Sci. USA 109, E3186–E3195 (2012).
Mitchell, C. et al. Dual role of CCR2 in the constitution and the resolution of liver fibrosis in mice. Am. J. Pathol. 174, 1766–1775 (2009).
Ramachandran, P. et al. Resolving the fibrotic niche of human liver cirrhosis at single-cell level. Nature 575, 512–518 (2019). Latest scRNA-seq paper from human cirrhotic liver dissects that unanticipated aspects of the cellular and molecular basis of liver fibrosis at a single-cell level.
Mandrekar, P., Ambade, A., Lim, A., Szabo, G. & Catalano, D. An essential role for monocyte chemoattractant protein-1 in alcoholic liver injury: regulation of proinflammatory cytokines and hepatic steatosis in mice. Hepatology 54, 2185–2197 (2011).
Dhanda, A. D. & Collins, P. L. Immune dysfunction in acute alcoholic hepatitis. World J. Gastroenterol. 21, 11904–11913 (2015).
Gao, B. & Xu, M. Chemokines and alcoholic hepatitis: are chemokines good therapeutic targets? Gut 63, 1683–1684 (2014). This is a well-written review summarizing the roles played by chemokines in the pathogenesis of alcoholic hepatitis.
Wasmuth, H. E., Tacke, F. & Trautwein, C. Chemokines in liver inflammation and fibrosis. Semin. Liver Dis. 30, 215–225 (2010). This is a nice review about the role of chemokines in the pathogenesis of liver cirrhosis.
Chen, W., Zhang, J., Fan, H. N. & Zhu, J. S. Function and therapeutic advances of chemokine and its receptor in nonalcoholic fatty liver disease. Ther. Adv. Gastroenterol. 11, 1756284818815184 (2018). This review is on the role of chemokines in the pathogenesis of NAFLD and the potential for therapeutic targeting of these chemokine pathways for the treatment of NAFLD.
Braunersreuther, V., Viviani, G. L., Mach, F. & Montecucco, F. Role of cytokines and chemokines in non-alcoholic fatty liver disease. World J. Gastroenterol. 18, 727–735 (2012).
Feng, D. The alteration of immune cells in the pathogenesis of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Liver Res. 4, 23–27 (2020).
Fahey, S., Dempsey, E. & Long, A. The role of chemokines in acute and chronic hepatitis C infection. Cell Mol. Immunol. 11, 25–40 (2014).
Fallahi, P. et al. Chemokines in the pathogenesis and as therapeutical markers and targets of HCV chronic infection and HCV extrahepatic manifestations. Curr. Drug Targets 18, 786–793 (2017).
Zhai, Y., Petrowsky, H., Hong, J. C., Busuttil, R. W. & Kupiec-Weglinski, J. W. Ischaemia–reperfusion injury in liver transplantation — from bench to bedside. Nat. Rev. Gastroenterol. Hepatol. 10, 79–89 (2013).
Yip, W. W. & Burt, A. D. Alcoholic liver disease. Semin. Diagn. Pathol. 23, 149–160 (2006).
Singal, A. K. & Shah, V. H. Current trials and novel therapeutic targets for alcoholic hepatitis. J. Hepatol. 70, 305–313 (2019). A review summarizing the novel therapeutic agents targeting various pathways in the pathophysiology of alcoholic hepatitis and the ongoing clinical trials in which some of these agents are being studied.
Xu, M.-J., Zhou, Z., Parker, R. & Gao, B. Targeting inflammation for the treatment of alcoholic liver disease. Pharmacol. Ther. 180, 77–89 (2017).
Rao, R. Endotoxemia and gut barrier dysfunction in alcoholic liver disease. Hepatology 50, 638–644 (2009). This review discusses a key concept of inter-organ crosstalk in the setting of alcoholic liver disease. A similar inter-organ crosstalk also exists between liver and other organs, such as adipose tissue, and in other disease conditions, such as NAFLD.
Bird, G. L., Sheron, N., Goka, A. K., Alexander, G. J. & Williams, R. S. Increased plasma tumor necrosis factor in severe alcoholic hepatitis. Ann. Intern. Med. 112, 917–920 (1990).
Sheron, N. et al. Circulating and tissue levels of the neutrophil chemotaxin interleukin-8 are elevated in severe acute alcoholic hepatitis, and tissue levels correlate with neutrophil infiltration. Hepatology 18, 41–46 (1993).
Khoruts, A., Stahnke, L., McClain, C. J., Logan, G. & Allen, J. I. Circulating tumor necrosis factor, interleukin-1 and interleukin-6 concentrations in chronic alcoholic patients. Hepatology 13, 267–276 (1991).
Fujita, T. & Narumiya, S. Roles of hepatic stellate cells in liver inflammation: a new perspective. Inflamm. Regen. 36, 1 (2016).
Seo, W. & Jeong, W. I. Hepatic non-parenchymal cells: master regulators of alcoholic liver disease? World J. Gastroenterol. 22, 1348–1356 (2016).
Cohen, J. I. & Nagy, L. E. Pathogenesis of alcoholic liver disease: interactions between parenchymal and non-parenchymal cells. J. Dig. Dis. 12, 3–9 (2011).
Affò, S. et al. CCL20 mediates lipopolysaccharide induced liver injury and is a potential driver of inflammation and fibrosis in alcoholic hepatitis. Gut 63, 1782 (2014).
Degre, D., Lemmers, A. & Gustot, T. Hepatic expression of CCL2 in alcoholic liver disease is associated with disease severity and neutrophil infiltrates. Clin. Exp. Immunol. 169, 302–310 (2012).
Ghosh Dastidar, S., Warner, J. B., Warner, D. R., McClain, C. J. & Kirpich, I. A. Rodent models of alcoholic liver disease: role of binge ethanol administration. Biomolecules 8, 3 (2018).
Bertola, A., Mathews, S., Ki, S. H., Wang, H. & Gao, B. Mouse model of chronic and binge ethanol feeding (the NIAAA model). Nat. Protoc. 8, 627–637 (2013).
Lazaro, R. et al. Osteopontin deficiency does not prevent but promotes alcoholic neutrophilic hepatitis in mice. Hepatology 61, 129–140 (2015).
Wieser, V. et al. Reversal of murine alcoholic steatohepatitis by pepducin-based functional blockade of interleukin-8 receptors. Gut 66, 930–938 (2017).
Altamirano, J. et al. A histologic scoring system for prognosis of patients with alcoholic hepatitis. Gastroenterology 146, 1231–1239.e1–6 (2014).
Taïeb, J. et al. Polymorphonuclear neutrophils are a source of hepatocyte growth factor in patients with severe alcoholic hepatitis. J. Hepatol. 36, 342–348 (2002).
Byun, J.-S., Suh, Y.-G., Yi, H.-S., Lee, Y.-S. & Jeong, W.-I. Activation of toll-like receptor 3 attenuates alcoholic liver injury by stimulating Kupffer cells and stellate cells to produce interleukin-10 in mice. J. Hepatol. 58, 342–349 (2013).
Younossi, Z. et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat. Rev. Gastroenterol. Hepatol. 15, 11 (2017).
Brunt, E. M. Pathology of fatty liver disease. Mod. Pathol. 20 (Suppl. 1), S40–S48 (2007).
Stephenson, K. et al. Updates on dietary models of nonalcoholic fatty liver disease: current studies and insights. Gene Expr. 18, 5–17 (2018).
Kanneganti, T. D. & Dixit, V. D. Immunological complications of obesity. Nat. Immunol. 13, 707–712 (2012).
Xu, H., Barnes, G. T. & Yang, Q. Chronic inflammation in fat plays a crucial role in the development of obesityrelated insulin resistance. J. Clin. Invest. 112, 1821–1830 (2003).
Makki, K., Froguel, P. & Wolowczuk, I. Adipose tissue in obesity-related inflammation and insulin resistance: cells, cytokines, and chemokines. ISRN Inflamm. 2013, 139239–139239 (2013).
Coppack, S. W. Pro-inflammatory cytokines and adipose tissue. Proc. Nutr. Soc. 60, 349–356 (2001).
Kanda, H., Tateya, S. & Tamori, Y. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J. Clin. Invest. 116, 1494–1505 (2006).
Tamura, Y., Sugimoto, M. & Murayama, T. C-C chemokine receptor 2 inhibitor improves diet-induced development of insulin resistance and hepatic steatosis in mice. J. Atheroscler. Thromb. 17, 219–228 (2010).
Sartipy, P. & Loskutoff, D. J. Monocyte chemoattractant protein 1 in obesity and insulin resistance. Proc. Natl Acad. Sci. USA 100, 7265–7270 (2003).
Reid, D. T. et al. Kupffer cells undergo fundamental changes during the development of experimental NASH and are critical in initiating liver damage and inflammation. PLoS ONE 11, e0159524 (2016).
Xiong, X. et al. Landscape of intercellular crosstalk in healthy and NASH liver revealed by single-cell secretome gene analysis. Mol. Cell 75, 644–660.e5 (2019).
Jaitin, D. A. et al. Lipid-associated macrophages control metabolic homeostasis in a trem2-dependent manner. Cell 178, 686–698.e14 (2019).
Krenkel, O. et al. Myeloid cells in liver and bone marrow acquire a functionally distinct inflammatory phenotype during obesity-related steatohepatitis. Gut 69, 551–563 (2020).
Perugorria, M. J. et al. Non-parenchymal TREM-2 protects the liver from immune-mediated hepatocellular damage. Gut 68, 533–546 (2019).
Berres, M. L. et al. Antagonism of the chemokine CCL5 ameliorates experimental liver fibrosis in mice. J. Clin. Invest. 120, 4129–4140 (2010).
Pérez-Martínez, L. et al. Maraviroc, a CCR5 antagonist, ameliorates the development of hepatic steatosis in a mouse model of non-alcoholic fatty liver disease (NAFLD). J. Antimicrob. Chemother. 69, 1903–1910 (2014).
Hu, Y. et al. Gut-derived lymphocyte recruitment to liver and induce liver injury in non-alcoholic fatty liver disease mouse model. J. Gastroenterol. Hepatol. 31, 676–684 (2016).
Zhang, X. et al. CXCL10 plays a key role as an inflammatory mediator and a non-invasive biomarker of non-alcoholic steatohepatitis. J. Hepatol. 61, 1365–1375 (2014).
Tomita, K. et al. CXCL10-mediates macrophage, but not other innate immune cells-associated inflammation in murine nonalcoholic steatohepatitis. Sci. Rep. 6, 28786 (2016).
Rouault, C., Pellegrinelli, V. & Schilch, R. Roles of chemokine ligand-2 (CXCL2) and neutrophils in influencing endothelial cell function and inflammation of human adipose tissue. Endocrinology 154, 1608–1614 (2013).
Jarrar, M. H. et al. Adipokines and cytokines in non-alcoholic fatty liver disease. Aliment. Pharmacol. Ther. 27, 412–421 (2008).
Tsuchida, T. & Friedman, S. L. Mechanisms of hepatic stellate cell activation. Nat. Rev. Gastroenterol. Hepatol. 14, 397 (2017).
Chu, P. S., Nakamoto, N. & Ebinuma, H. C-C motif chemokine receptor 9 positive macrophages activate hepatic stellate cells and promote liver fibrosis in mice. Hepatology 58, 337–350 (2013).
Ehling, J. et al. CCL2-dependent infiltrating macrophages promote angiogenesis in progressive liver fibrosis. Gut 63, 1960 (2014).
Marra, F., Romanelli, R. G. & Giannini, C. Monocyte chemotactic protein-1 as a chemoattractant for human hepatic stellate cells. Hepatology 29, 140–148 (1999).
Seki, E., de Minicis, S. & Inokuchi, S. CCR2 promotes hepatic fibrosis in mice. Hepatology 50, 185–197 (2009).
Nakamoto, N. et al. CCR9+ macrophages are required for acute liver inflammation in mouse models of hepatitis. Gastroenterology 142, 366–376 (2012).
Chen, L., Zhang, Q., Yu, C., Wang, F. & Kong, X. Functional roles of CCL5/RANTES in liver disease. Liver Res. 4, 28–34 (2020).
Seki, E., De Minicis, S. & Gwak, G. Y. CCR1 and CCR5 promote hepatic fibrosis in mice. J. Clin. Invest. 119, 1858–1870 (2009).
Heinrichs, D., Berres, M. L. & Nellen, A. The chemokine CCL3 promotes experimental liver fibrosis in mice. PLoS ONE 8, 66106 (2013).
Tacke, F. & Zimmermann, H. W. Macrophage heterogeneity in liver injury and fibrosis. J. Hepatol. 60, 1090–1096 (2014).
Oo, Y. H., Banz, V. & Kavanagh, D. CXCR3-dependent recruitment and CCR6-mediated positioning of Th-17 cells in the inflamed liver. J. Hepatol. 57, 1044–1051 (2012).
Hintermann, E., Bayer, M. & Pfeilschifter, J. M. CXCL10 promotes liver fibrosis by prevention of NK cell mediated hepatic stellate cell inactivation. J. Autoimmun. 35, 424–435 (2010).
Hammerich, L. et al. Chemokine receptor CCR6-dependent accumulation of γδ T cells in injured liver restricts hepatic inflammation and fibrosis. Hepatology 59, 630–642 (2014).
Wehr, A., Baeck, C. & Heymann, F. Chemokine receptor CXCR6-dependent hepatic NK T Cell accumulation promotes inflammation and liver fibrosis. J. Immunol. 190, 5226–5236 (2013).
Karlmark, K. R., Zimmermann, H. W. & Roderburg, C. The fractalkine receptor CX(3)CR1 protects against liver fibrosis by controlling differentiation and survival of infiltrating hepatic monocytes. Hepatology 52, 1769–1782 (2010).
Aoyama, T., Inokuchi, S., Brenner, D. A. & Seki, E. CX3CL1-CX3CR1 interaction prevents carbon tetrachloride-induced liver inflammation and fibrosis in mice. Hepatology 52, 1390–1400 (2010).
Llovet, J. M. et al. Hepatocellular carcinoma. Nat. Rev. Dis. Prim. 2, 16018 (2016).
Hou, J., Zhang, H., Sun, B. & Karin, M. The immunobiology of hepatocellular carcinoma in humans and mice: basic concepts and therapeutic implications. J. Hepatol. 72, 167–182 (2020). This review summarizes the current understanding of HCC onco-immunology with an emphasis on how these mechanisms might be a basis for HCC-targeting immunotherapy.
Lim, S. Y., Yuzhalin, A. E., Gordon-Weeks, A. N. & Muschel, R. J. Targeting the CCL2-CCR2 signaling axis in cancer metastasis. Oncotarget 7, 28697–28710 (2016).
Chew, V. et al. Inflammatory tumour microenvironment is associated with superior survival in hepatocellular carcinoma patients. J. Hepatol. 52, 370–379 (2010).
Chen, K. J., Lin, S. Z. & Zhou, L. Selective recruitment of regulatory T cell through CCR6-CCL20 in hepatocellular carcinoma fosters tumor progression and predicts poor prognosis. PLoS ONE 6, 24671 (2011).
Oo, Y. H. et al. Distinct roles for CCR4 and CXCR3 in the recruitment and positioning of regulatory T cells in the inflamed human liver. J. Immunol. 184, 2886–2898 (2010).
Ren, Y., Poon, R. T. & Tsui, H. T. Interleukin-8 serum levels in patients with hepatocellular carcinoma: correlations with clinicopathological features and prognosis. Clin. Cancer Res. 9, 5996–6001 (2003).
Zhou, S. L., Dai, Z. & Zhou, Z. J. Overexpression of CXCL5 mediates neutrophil infiltration and indicates poor prognosis for hepatocellular carcinoma. Hepatology 56, 2242–2254 (2012).
Li, L. et al. CXCR2–CXCL1 axis is correlated with neutrophil infiltration and predicts a poor prognosis in hepatocellular carcinoma. J. Exp. Clin. Cancer Res. 34, 129 (2015).
Liu, K. et al. Targeting the vasculature in hepatocellular carcinoma treatment: Starving versus normalizing blood supply. Clin. Transl Gastroenterol. 8, e98 (2017).
Yamada, K. et al. CXCL12–CXCR7 axis is important for tumor endothelial cell angiogenic property. Int. J. Cancer 137, 2825–2836 (2015).
Zheng, K. et al. Chemokine receptor CXCR7 regulates the invasion, angiogenesis and tumor growth of human hepatocellular carcinoma cells. J. Exp. Clin. Cancer Res. 29, 31 (2010).
Liu, J.-Y. et al. Delivery of siRNA using CXCR4-targeted nanoparticles modulates tumor microenvironment and achieves a potent antitumor response in liver cancer. Mol. Ther. 23, 1772–1782 (2015).
Zhu, B. et al. Activated hepatic stellate cells promote angiogenesis via interleukin-8 in hepatocellular carcinoma. J. Transl Med. 13, 365 (2015).
Lasagni, L. et al. An alternatively spliced variant of CXCR3 mediates the inhibition of endothelial cell growth induced by IP-10, Mig, and I-TAC, and acts as functional receptor for platelet factor 4. J. Exp. Med. 197, 1537–1549 (2003).
Sutton, A., Friand, V. & Brule-Donneger, S. Stromal cell derived factor-1/chemokine (C-X-C motif) ligand 12 stimulates human hepatoma cell growth, migration, and invasion. Mol. Cancer Res. 5, 21–33 (2007).
Xiang, Z. L., Zeng, Z. C. & Tang, Z. Y. Chemokine receptor CXCR4 expression in hepatocellular carcinoma patients increases the risk of bone metastases and poor survival. BMC Cancer 9, 176 (2009).
Armstrong, D. & Cameron, R. G. Comparison of liver cancer and nodules induced in rats by deoxycholic acid diet with or without prior initiation. Cancer Lett. 57, 153–157 (1991).
Ma, C. et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science 360, eaan5931 (2018).
Mossanen, J. C. et al. CXCR6 inhibits hepatocarcinogenesis by promoting natural killer T- and CD4+ T-cell-dependent control of senescence. Gastroenterology 156, 1877–1889.e4 (2019).
Ehling, J. & Tacke, F. Role of chemokine pathways in hepatobiliary cancer. Cancer Lett. 379, 173–183 (2016).
Park, S. H. & Rehermann, B. Immune responses to HCV and other hepatitis viruses. Immunity 40, 13–24 (2014).
Hu, J., Lin, Y. Y., Chen, P. J., Watashi, K. & Wakita, T. Cell and animal models for studying hepatitis B virus infection and drug development. Gastroenterology 156, 338–354 (2019).
Burm, R., Collignon, L., Mesalam, A. A. & Meuleman, P. Animal models to study hepatitis C virus infection. Front. Immunol. 9, 1032 (2018).
Rehermann, B. Pathogenesis of chronic viral hepatitis: differential roles of T cells and NK cells. Nat. Med. 19, 859–868 (2013).
Riezu-Boj, J. I., Larrea, E. & Aldabe, R. Hepatitis C virus induces the expression of CCL17 and CCL22 chemokines that attract regulatory T cells to the site of infection. J. Hepatol. 54, 422–431 (2011).
Berres, M. L., Trautwein, C. & Schmeding, M. Serum chemokine CXC ligand 10 (CXCL10) predicts fibrosis progression after liver transplantation for hepatitis C infection. Hepatology 53, 596–603 (2011).
Tacke, F., Zimmermann, H. W. & Berres, M. L. Serum chemokine receptor CXCR3 ligands are associated with progression, organ dysfunction and complications of chronic liver diseases. Liver Int. 31, 840–849 (2011).
Vranjkovic, A. et al. Direct-acting antiviral treatment of HCV infection does not resolve the dysfunction of circulating CD8+ T-cells in advanced liver disease. Front. Immunol. https://doi.org/10.3389/fimmu.2019.01926 (2019).
Umemura, T. et al. Quantitative analysis of serum chemokines associated with treatment failure of direct-acting antivirals in chronic hepatitis C. Cytokine 111, 357–363 (2018).
Hengst, J. et al. Direct-acting antiviral–induced hepatitis C virus clearance does not completely restore the altered cytokine and chemokine milieu in patients with chronic hepatitis C. J. Infect. Dis. 214, 1965–1974 (2016).
Yoshio, S. et al. Cytokine and chemokine signatures associated with hepatitis B surface antigen loss in hepatitis B patients. JCI Insight 3, e122268 (2018).
Keating, S. M., Heitman, J. D. & Wu, S. Cytokine and chemokine responses in the acute phase of hepatitis B virus replication in naive and previously vaccinated blood and plasma donors. J. Infect. Dis. 209, 845–854 (2014).
Kakimi, K. et al. Blocking chemokine responsive to gamma-2/interferon (IFN)-gamma inducible protein and monokine induced by IFN-gamma activity in vivo reduces the pathogenetic but not the antiviral potential of hepatitis B virus-specific cytotoxic T lymphocytes. J. Exp. Med. 194, 1755–1766 (2001).
Maini, M. K. et al. Direct ex vivo analysis of hepatitis B virus-specific CD8+ T cells associated with the control of infection. Gastroenterology 117, 1386–1396 (1999).
Tan, A. T., Koh, S. & Goh, W. A longitudinal analysis of innate and adaptive immune profile during hepatic flares in chronic hepatitis B. J. Hepatol. 52, 330–339 (2010).
Brass, A. & Brenndorfer, E. D. The role of chemokines in hepatitis C virus-mediated liver disease. Int. J. Mol. Sci. 15, 4747–477 (2014).
Ali, J. M. et al. Analysis of ischemia/reperfusion injury in time-zero biopsies predicts liver allograft outcomes. Liver Transplant. 21, 487–499 (2015).
Degli Esposti, D. et al. Ischemic preconditioning induces autophagy and limits necrosis in human recipients of fatty liver grafts, decreasing the incidence of rejection episodes. Cell Death Dis. 2, e111 (2011).
Wilson, G. C. et al. CXC chemokines function as a rheostat for hepatocyte proliferation and liver regeneration. PLoS ONE 10, e0120092 (2015).
Oliveira, T. H. C. D., Marques, P. E., Proost, P. & Teixeira, M. M. M. Neutrophils: a cornerstone of liver ischemia and reperfusion injury. Lab. Invest. 98, 51–62 (2018).
Bertini, R. et al. Noncompetitive allosteric inhibitors of the inflammatory chemokine receptors CXCR1 and CXCR2: prevention of reperfusion injury. Proc. Natl Acad. Sci. USA 101, 11791–11796 (2004).
Colletti, L. M. et al. The role of cytokine networks in the local liver injury following hepatic ischemia/reperfusion in the rat. Hepatology 23, 506–514 (1996).
Lentsch, A. B., Yoshidome, H., Cheadle, W. G., Miller, F. N. & Edwards, M. J. Chemokine involvement in hepatic ischemia/reperfusion injury in mice: roles for macrophage inflammatory protein-2 and Kupffer cells. Hepatology 27, 507–512 (1998).
Selzner, N. et al. Mouse livers with macrosteatosis are more susceptible to normothermic ischemic injury than those with microsteatosis. J. Hepatol. 44, 694–701 (2006).
Mollica Poeta, V., Massara, M., Capucetti, A. & Bonecchi, R. Chemokines and chemokine receptors: new targets for cancer immunotherapy. Front. Immunol. 10, 379 (2019).
Balkwill, F. Cancer and the chemokine network. Nat. Rev. Cancer 4, 540–550 (2004).
Sahin, H. et al. Proapoptotic effects of the chemokine, CXCL 10 are mediated by the noncognate receptor TLR4 in hepatocytes. Hepatology 57, 797–805 (2013).
Zeremski, M. et al. Peripheral CXCR3-associated chemokines as biomarkers of fibrosis in chronic hepatitis C virus infection. J. Infect. Dis. 200, 1774–1780 (2009).
Zeremski, M. et al. Intrahepatic levels of CXCR3-associated chemokines correlate with liver inflammation and fibrosis in chronic hepatitis C. Hepatology 48, 1440–1450 (2008).
Zhou, Y. et al. Hepatitis B virus protein X-induced expression of the CXC chemokine IP-10 is mediated through activation of NF-κB and increases migration of leukocytes. J. Biol. Chem. 285, 12159–12168 (2010).
Haukeland, J. W. et al. Systemic inflammation in nonalcoholic fatty liver disease is characterized by elevated levels of CCL2. J. Hepatol. 44, 1167–1174 (2006).
Sehrawat, T. S., Liu, M. & Shah, V. H. The knowns and unknowns of treatment for alcoholic hepatitis. Lancet Gastroenterol. Hepatol. 5, 494–506 (2020).
Kuang, D. M. et al. Peritumoral neutrophils link inflammatory response to disease progression by fostering angiogenesis in hepatocellular carcinoma. J. Hepatol. 54, 948–955 (2011).
Desurmont, T. et al. Overexpression of chemokine receptor CXCR2 and ligand CXCL7 in liver metastases from colon cancer is correlated to shorter disease-free and overall survival. Cancer Sci. 106, 262–269 (2015).
Fisher, N. C., Neil, D. A., Williams, A. & Adams, D. H. Serum concentrations and peripheral secretion of the beta chemokines monocyte chemoattractant protein 1 and macrophage inflammatory protein 1alpha in alcoholic liver disease. Gut 45, 416–420 (1999).
Devalaraja, M. N., McClain, C. J., Barve, S., Vaddi, K. & Hill, D. B. Increased monocyte MCP-1 production in acute alcoholic hepatitis. Cytokine 11, 875–881 (1999).
Schwabe, R. F., Bataller, R. & Brenner, D. A. Human hepatic stellate cells express CCR5 and RANTES to induce proliferation and migration. Am. J. Physiol. Gastrointest. Liver Physiol. 285, G949–G958 (2003).
Hanson, A. et al. Chemokine ligand 20 (CCL20) expression increases with NAFLD stage and hepatic stellate cell activation and is regulated by miR-590-5p. Cytokine 123, 154789 (2019).
de Graaf, K. L. et al. NI-0801, an anti-chemokine (C-X-C motif) ligand 10 antibody, in patients with primary biliary cholangitis and an incomplete response to ursodeoxycholic acid. Hepatol. Commun. 2, 492–503 (2018).
Richard Parker, M. W. et al. Therapeutic use of a clinical stage CCR2 inhibitor, CCX872, in obesity-associated steatohepatitis. Lancet https://doi.org/10.1016/S0140-6736(14)60341-X (2014).
Linehan, D. et al. Overall survival in a trial of orally administered CCR2 inhibitor CCX872 in locally advanced/metastatic pancreatic cancer: correlation with blood monocyte counts. J. Clin. Oncol. 36, 92–92 (2018).
Baeck, C. et al. Pharmacological inhibition of the chemokine CCL2 (MCP-1) diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury. Gut 61, 416–426 (2012). This study demonstrated the blocking of monocyte–macrophage infiltration post-liver injury via MCP1 inhibition in vivo. Such early studies helped develop interest in studying chemokine inhibition as a novel therapeutic approach.
Cheng, Y., Ma, X. L., Wei, Y. Q. & Wei, X. W. Potential roles and targeted therapy of the CXCLs/CXCR2 axis in cancer and inflammatory diseases. Biochim. Biophys. Acta Rev. Cancer 1871, 289–312 (2019).
Friedman, S. L. et al. A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis. Hepatology 67, 1754–1767 (2018). A landmark double-blinded and multicentre RCT for the potential therapeutic cenicriviroc. Based on positive efficacy signal and safety profile, this trial has led to the establishment of a phase III trial.
Ratziu, V. et al. Cenicriviroc treatment for adults with nonalcoholic steatohepatitis and fibrosis: final analysis of the phase 2b CENTAUR study. Hepatology 72, 892–905 (2020). This is a nice paper about a landmark clinical trial for recent NASH therapeutics.
Gilan, O. et al. Selective targeting of BD1 and BD2 of the BET proteins in cancer and immunoinflammation. Science 368, 387–394 (2020). This study identifies the specificity of blocking BD1 and BD2 domains. iBET-BD1 and iBET-BD2 were both shown to have immunomodulatory activity but iBET-BD2 inhibition with GSK620 was shown to ameliorate inflammatory injury.
Filippakopoulos, P. & Knapp, S. Next-generation epigenetic inhibitors. Science 368, 367–368 (2020). A comprehensive and current review of new advances in promising epigenetic inhibitors; it describes roles for bromodomains in transcription and various ways that they can be targeted.
Qi, J. & Shi, Y. Selective targeting of different bromodomains by small molecules. Cancer Cell 37, 764–766 (2020).
Berthon, C. et al. Bromodomain inhibitor OTX015 in patients with acute leukaemia: a dose-escalation, phase 1 study. Lancet Haematol. 3, e186–e195 (2016).
Dawson, M. et al. A phase I study of GSK525762, a selective bromodomain (BRD) and extra terminal protein (BET) inhibitor: results from part 1 of Phase I/II open label single agent study in patients with acute myeloid leukemia (AML). Blood 130, 1377 (2017).
Jophlin, L. L., Cao, S. & Shah, V. H. The transcriptome of hepatic fibrosis revealed by single cell RNA sequencing. Hepatology 71, 1865–1867 (2020).
Kar, S., Paglialunga, S., Jaycox, S. H., Islam, R. & Paredes, A. H. Assay validation and clinical performance of chronic inflammatory and chemokine biomarkers of NASH fibrosis. PLoS ONE 14, e0217263 (2019).
Nio, Y., Yamauchi, T. & Iwabu, M. Monocyte chemoattractant protein-1 (MCP-1) deficiency enhances alternatively activated M2 macrophages and ameliorates insulin resistance and fatty liver in lipoatrophic diabetic A-ZIP transgenic mice. Diabetologia 55, 3350–3358 (2012).
Kitade, H., Sawamoto, K. & Nagashimada, M. CCR5 plays a critical role in obesity-induced adipose tissue inflammation and insulin resistance by regulating both macrophage recruitment and M1/M2 status. Diabetes 61, 1680–1690 (2012).
Zhang, X. et al. CXC chemokine receptor 3 promotes steatohepatitis in mice through mediating inflammatory cytokines, macrophages and autophagy. J. Hepatol. 64, 160–170 (2016).
Ibrahim, S. H. et al. Mixed lineage kinase 3 mediates release of C-X-C motif ligand 10-bearing chemotactic extracellular vesicles from lipotoxic hepatocytes. Hepatology 63, 731–744 (2016). An elegant study describing chemokine-bearing extracellular vesicles as chemoattractants for macrophages in liver injury models; extracellular vesicles are also currently being explored both as biomarkers and as therapeutic delivery agents.
Mohs, A. et al. Functional role of CCL5/RANTES for HCC progression during chronic liver disease. J. Hepatol. 66, 743–753 (2017).
Kaffe, E. et al. β-Catenin and interleukin-1β-dependent chemokine (C-X-C motif) ligand 10 production drives progression of disease in a mouse model of congenital hepatic fibrosis. Hepatology 67, 1903–1919 (2018).
Wiedemann, G. M. et al. Peritumoural CCL1 and CCL22 expressing cells in hepatocellular carcinomas shape the tumour immune infiltrate. Pathology 51, 586–592 (2019).
Li, X. et al. Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma. Gut 66, 157–167 (2017).
Bartneck, M. et al. The CCR2+ macrophage subset promotes pathogenic angiogenesis for tumor vascularization in fibrotic livers. Cell Mol. Gastroenterol. Hepatol. 7, 371–390 (2019).
Zhu, F. et al. Tumor-associated macrophage or chemokine ligand CCL17 positively regulates the tumorigenesis of hepatocellular carcinoma. Med. Oncol. 33, 17 (2016).
He, H. et al. CCR6+ B lymphocytes responding to tumor cell-derived CCL20 support hepatocellular carcinoma progression via enhancing angiogenesis. Am. J. Cancer Res. 7, 1151–1163 (2017).
Hilscher, M. B. et al. Mechanical stretch increases expression of CXCL1 in liver sinusoidal endothelial cells to recruit neutrophils, generate sinusoidal microthombi, and promote portal hypertension. Gastroenterology 157, 193–209.e9 (2019). Although liver diseases such as Budd–Chiari syndrome are mostly considered to be pressure-induced injuries, this study explains how chemokines such as CXCL1 might have a role in the development of portal hypertension in vivo as well as in patients with cardiac cirrhosis.
Work on chemokines in the laboratory of V.H.S. is supported by NIH grants AA21171 and DK59615.
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Cao, S., Liu, M., Sehrawat, T.S. et al. Regulation and functional roles of chemokines in liver diseases. Nat Rev Gastroenterol Hepatol (2021). https://doi.org/10.1038/s41575-021-00444-2