Roles for Chemokines in Liver Disease

Sustained hepatic inflammation is an important factor in progression of chronic liver diseases, including hepatitis C or non-alcoholic steatohepatitis. Liver inflammation is regulated by chemokines, which regulate the migration and activities of hepatocytes, Kupffer cells, hepatic stellate cells, endothelial cells, and circulating immune cells. However, the effects of the different chemokines and their receptors vary during pathogenesis of different liver diseases. During development of chronic viral hepatitis, CCL5 and CXCL10 regulate the cytopathic versus antiviral immune responses of T cells and natural killer cells. During development of nonalcoholic steatohepatitis, CCL2 and its receptor are up-regulated in the liver, where they promote macrophage accumulation, inflammation, fibrosis, and steatosis, as well as in adipose tissue. CCL2 signaling thereby links hepatic and systemic inflammation related to metabolic disorders and insulin resistance. Several chemokine signaling pathways also promote hepatic fibrosis. Recent studies have shown that other chemokines and immune cells have anti-inflammatory and antifibrotic activities. Chemokines and their receptors can also contribute to the pathogenesis of hepatocellular carcinoma, promoting proliferation of cancer cells, the inflammatory microenvironment of the tumor, evasion of the immune response, and angiogenesis. We review the roles of different chemokines in the pathogenesis of liver diseases and their potential use as biomarkers or therapeutic targets. Sustained hepatic inflammation is an important factor in progression of chronic liver diseases, including hepatitis C or non-alcoholic steatohepatitis. Liver inflammation is regulated by chemokines, which regulate the migration and activities of hepatocytes, Kupffer cells, hepatic stellate cells, endothelial cells, and circulating immune cells. However, the effects of the different chemokines and their receptors vary during pathogenesis of different liver diseases. During development of chronic viral hepatitis, CCL5 and CXCL10 regulate the cytopathic versus antiviral immune responses of T cells and natural killer cells. During development of nonalcoholic steatohepatitis, CCL2 and its receptor are up-regulated in the liver, where they promote macrophage accumulation, inflammation, fibrosis, and steatosis, as well as in adipose tissue. CCL2 signaling thereby links hepatic and systemic inflammation related to metabolic disorders and insulin resistance. Several chemokine signaling pathways also promote hepatic fibrosis. Recent studies have shown that other chemokines and immune cells have anti-inflammatory and antifibrotic activities. Chemokines and their receptors can also contribute to the pathogenesis of hepatocellular carcinoma, promoting proliferation of cancer cells, the inflammatory microenvironment of the tumor, evasion of the immune response, and angiogenesis. We review the roles of different chemokines in the pathogenesis of liver diseases and their potential use as biomarkers or therapeutic targets. Virtually all liver diseases are characterized by the presence of an inflammatory response. Chemokines and their corresponding chemokine receptors are key players in orchestrating the sequential influx of immune cells into damaged or disease organs, driving inflammatory responses to specific triggers. The chemokine system exerts a key role in the development of hepatic inflammation and ensuing wound healing responses, which can lead to either resolution or maladaptive responses with chronic inflammation, tissue scarring (fibrosis), and development of clinically manifest liver disease.1Zimmermann 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. 2011; 10: 509-536Crossref PubMed Google Scholar Hence, chemokines are important determinants in the pathogenesis and outcome of hepatic disease. Chemokines are small molecular weight proteins (8–13 kilodaltons) and categorized into 4 different families (CC, CXC, CX3C, C) based on the presence of NH2 terminal cysteine motifs.2Charo I.F. Ransohoff R.M. The many roles of chemokines and chemokine receptors in inflammation.N Engl J Med. 2006; 354: 610-621Crossref PubMed Scopus (1910) Google Scholar Altogether, the chemokine system comprises genes encoding 50 chemokine ligands and 20 cognate chemokine receptors, of which several have been identified as relevant in the context of liver diseases (Table 1).3Zlotnik A. Yoshie O. Chemokines: a new classification system and their role in immunity.Immunity. 2000; 12: 121-127Abstract Full Text Full Text PDF PubMed Google ScholarTable 1Relevant Chemokines in the Pathogenesis of Liver Diseases and Their Corresponding Receptors (Selection)ChemokineAlternative name(s)Main chemokine receptor(s)Target cell(s)Suggested involvement in liver diseaseCCL1I-309, TCA-3CCR8Monocytes/macrophagesFibrosisCCL2MCP-1CCR2Monocytes/macrophages, HSCsInitiation of inflammation, fibrosis, NAFLD/NASHCCL3MIP-1αCCR1, CCR5NK, Th1, CD8 THCV, HBV, NAFLD/NASH, fibrosisCCL4MIP-1βCCR1, CCR5NK, Th1, CD8 THCV, HBV, NAFLD/NASH, fibrosisCCL5RANTESCCR1, CCR5NK, Th1, CD8 T, HSCsHCV, HBV, NAFLD/NASH, fibrosisCCL17TARCCCR4TregHCVCCL19ELCCCR7CD8 T, DCsHCVCCL20MIP-3αCCR6γδ T, Th17, HSCsCholestatic, HCV, alcohol, fibrosisCCL21SLCCCR7CD8 T, DCsHCV, fibrosisCCL22MDCCCR4TregHCVCCL25TECKCCR9Monocytes/macrophages, HSCsFibrosisCXCL1Gro-αCXCR2Neutrophils, monocytesInitiation of inflammation, alcoholCXCL2Gro-βCXCR2Neutrophils, monocytesInitiation of inflammation, alcoholCXCL5ENA-78CXCR2NeutrophilsAlcohol, fibrosisCXCL6GCP-2CXCR1, CXCR2Neutrophils, monocytesalcoholCXCL8IL-8CXCR1, CXCR2Neutrophils, monocytesInitiation of inflammation, alcohol, HBVCXCL9MIGCXCR3NK, Th1, Th17HCV, fibrosisCXCL10IP-10CXCR3NK, Th1, Th17, HSCsCholestatic, HCV, HBV, fibrosisCXCL11I-TACCXCR3NK, Th1, Th17HCV, fibrosisCXCL12SDF-1CXCR4, CXCR7HSCs, LSECs, HCCsFibrosis, regeneration, HCCCXCL13BCA-1CXCR5B cellsHCVCXCL16SRPSOXCXCR6NKT cellsHCV, fibrosisCX3CL1Fractalkine, neurotactinCX3CR1Monocytes/macrophagesHCV, fibrosisDC, dendritic cell; NAFLD, nonalcoholic fatty liver disease; Treg, regulatory T cell. Open table in a new tab DC, dendritic cell; NAFLD, nonalcoholic fatty liver disease; Treg, regulatory T cell. Chemokine receptors are typical G protein–coupled transmembrane proteins. Upon binding of the cognate chemokine ligand, Gα1 and Gβ-γ subunits dissociate and activate phosphatidylinositol 3-kinase and small Rho guanosine triphosphatase downstream pathways, resulting in cellular calcium influx.4Mellado M. Rodriguez-Frade J.M. Manes S. et al.Chemokine signaling and functional responses: the role of receptor dimerization and TK pathway activation.Annu Rev Immunol. 2001; 19: 397-421Crossref PubMed Scopus (285) Google Scholar Downstream cascades trigger conformational changes of leukocyte integrins that promote interactions with adhesion molecules expressed on endothelial cells, such as intercellular adhesion molecule and vascular cell adhesion molecule, and thereby facilitate leukocyte adhesion and subsequent extravasation.5Oo Y.H. Shetty S. Adams D.H. The role of chemokines in the recruitment of lymphocytes to the liver.Dig Dis. 2010; 28: 31-44Crossref PubMed Scopus (94) Google Scholar Secreted chemokines have a high affinity to glycosaminoglycans bound to extracellular matrix and endothelial surface. This facet favors that chemokines are locally immobilized and retained, which creates a concentration gradient allowing a coordinated trafficking of leukocytes toward injured tissue.6Proudfoot A.E. Handel T.M. Johnson Z. et al.Glycosaminoglycan binding and oligomerization are essential for the in vivo activity of certain chemokines.Proc Natl Acad Sci U S A. 2003; 100: 1885-1890Crossref PubMed Scopus (0) Google Scholar Chemokines are not only implicated in immune cell recruitment during inflammation but also contribute to immune surveillance, direct cells to target organs in homeostasis, and exert pleiotropic effects on nonimmune cells, for instance, directly influencing the functionality of fibrogenic stellate cells.7Wasmuth H.E. Tacke F. Trautwein C. Chemokines in liver inflammation and fibrosis.Semin Liver Dis. 2010; 30: 215-225Crossref PubMed Scopus (124) Google Scholar Chemokine receptors are typically expressed by various leukocyte subsets, and immune cells generally carry different sets of chemokine receptors. Interestingly, chemokine receptors mainly involved in modulating inflammatory responses (eg, CCR1, CCR2, CCR5, CXCR3) frequently ligate numerous chemokines, whereas prevailing “homeostatic” receptors (eg, CXCR4, CXCR5) appear more restricted in binding only 1 or 2 ligands.1Zimmermann 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. 2011; 10: 509-536Crossref PubMed Google Scholar These facts denote the enormous complexity of the chemokine network in homeostasis and inflammation. However, the common paradigm of chemokine “redundancy” due to the high ratio of chemokines versus receptors is more and more refuted,8Schall T.J. Proudfoot A.E. Overcoming hurdles in developing successful drugs targeting chemokine receptors.Nat Rev Immunol. 2011; 11: 355-363Crossref PubMed Scopus (242) Google Scholar because distinct functions of one particular chemokine cannot be fully replaced by another ligand. In fact, various chemokines can induce different and even antithetic biological tasks although acting at the same receptor. In conjunction with the thorough evaluation of human samples, different mouse models of experimental liver injury have been extensively investigated to delineate the molecular mechanisms of initiating inflammatory responses in the liver, the kinetics of infiltration by specific immune cell subsets, and the functional role of chemokines in the course and outcome of disease (Figure 1). Hepatic macrophages, traditionally denoted Kupffer cells, hold a central position as sensors of tissue stress, malfunction, or injury.9Medzhitov R. Schneider D.S. Soares M.P. Disease tolerance as a defense strategy.Science. 2012; 335: 936-941Crossref PubMed Scopus (938) Google Scholar Together with liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs) and local immune cells (in particular, unconventional T cells, natural killer [NK] cells, and hepatic dendritic cells), Kupffer cells constitute the nonparenchymal liver cells, which are both important sources and responders to chemokines. Infectious or noninfectious damage of hepatocytes results in the release of various danger signals, termed pathogen- or danger-associated molecular patterns, which bind to Toll-like receptor (TLR) 4 and other TLRs on Kupffer cells and promote release of proinflammatory cytokines (eg, tumor necrosis factor [TNF]), chemokines, and reactive oxygen and nitrogen species.10Liaskou E. Wilson D.V. Oo Y.H. Innate immune cells in liver inflammation.Mediators Inflamm. 2012; 2012: 949157Crossref PubMed Scopus (134) Google Scholar Kupffer cell–secreted TNF is considered central in the augmentation of liver injury, mainly by inducing hepatocyte apoptosis but also by deterioration of hepatic microcirculation through swelling and activation of endothelial cells with subsequent sinusoidal platelet aggregation and facilitation of the entry of peripheral immune cells. Activated Kupffer cells secrete interleukin (IL)-1β and CXC chemokines such as CXCL1, CXCL2, and CXCL8 (IL-8). CXCL1, CXCL2, and CXCL8 are key chemokines to attract neutrophils, mainly via the chemokine receptors CXCR1 and CXCR2, which release reactive oxygen species as well as proteases and thereby evoke hepatocyte necrosis.1Zimmermann 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. 2011; 10: 509-536Crossref PubMed Google Scholar In parallel, Kupffer cells, injured hepatocytes, and activated HSCs secrete high levels of CCL2, which promotes the hepatic accumulation of bone marrow–derived CCR2-expressing monocytes that massively expand the local macrophage pool.11Dambach D.M. Watson L.M. Gray K.R. et al.Role of CCR2 in macrophage migration into the liver during acetaminophen-induced hepatotoxicity in the mouse.Hepatology. 2002; 35: 1093-1103Crossref PubMed Scopus (203) Google Scholar, 12Seki E. De Minicis S. Osterreicher C.H. et al.TLR4 enhances TGF-beta signaling and hepatic fibrosis.Nat Med. 2007; 13: 1324-1332Crossref PubMed Scopus (1346) Google Scholar, 13Karlmark K.R. Weiskirchen R. Zimmermann H.W. et al.Hepatic recruitment of the inflammatory Gr1+ monocyte subset upon liver injury promotes hepatic fibrosis.Hepatology. 2009; 50: 261-274Crossref PubMed Scopus (516) Google Scholar Mechanistically, CCL2 appears especially important for the egress from the bone marrow into circulation of inflammatory monocytes, which express high levels of the surface protein Ly-6C in mice,14Serbina N.V. Pamer E.G. Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2.Nat Immunol. 2006; 7: 311-317Crossref PubMed Scopus (1109) Google Scholar allowing their accumulation at sites of injury in the liver (Figure 1). The subsequent functionality of monocyte-derived macrophages, however, not only depends on their CCR2-dependent recruitment. Other chemokines involved in monocyte/macrophage functionality are CCL1 and CCL25, which promote recruitment of inflammatory (TNF-producing) monocytes via CCR8 and CCR9, respectively,15Heymann F. Hammerich L. Storch D. et al.Hepatic macrophage migration and differentiation critical for liver fibrosis is mediated by the chemokine receptor C-C motif chemokine receptor 8 in mice.Hepatology. 2012; 55: 898-909Crossref PubMed Scopus (111) Google Scholar, 16Nakamoto N. Ebinuma H. Kanai T. et al.CCR9+ macrophages are required for acute liver inflammation in mouse models of hepatitis.Gastroenterology. 2012; 142: 366-376Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar and CX3CL1, which appears to rather limit inflammatory functions of monocytes/macrophages and prolong their survival, thereby counterbalancing inflammatory chemokine pathways.17Karlmark K.R. Zimmermann H.W. Roderburg C. et al.The fractalkine receptor CX(3)CR1 protects against liver fibrosis by controlling differentiation and survival of infiltrating hepatic monocytes.Hepatology. 2010; 52: 1769-1782Crossref PubMed Scopus (162) Google Scholar Compared with other organs in the body, the liver is also highly enriched in lymphocyte constituents of the innate immune system,18Racanelli V. Rehermann B. The liver as an immunological organ.Hepatology. 2006; 43: S54-S62Crossref PubMed Scopus (792) Google Scholar and chemokines are considered essential for their pathogenic involvement in liver diseases. NK cells represent approximately 30% of total intrahepatic lymphocytes with either immunomodulatory or direct cytotoxic functions and respond to several chemokine signals, including CCL5 via CCR1 and CXCL9/CXCL10 via CXCR3.5Oo Y.H. Shetty S. Adams D.H. The role of chemokines in the recruitment of lymphocytes to the liver.Dig Dis. 2010; 28: 31-44Crossref PubMed Scopus (94) Google Scholar, 19Robertson M.J. Role of chemokines in the biology of natural killer cells.J Leukoc Biol. 2002; 71: 173-183Crossref PubMed Google Scholar, 20Ajuebor M.N. Wondimu Z. Hogaboam C.M. et al.CCR5 deficiency drives enhanced natural killer cell trafficking to and activation within the liver in murine T cell-mediated hepatitis.Am J Pathol. 2007; 170: 1975-1988Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar NKT cells express markers of NK and T cells and constantly patrol the liver in homeostasis by crawling along the sinusoids. Endothelial expression of the chemokine CXCL16, corresponding to CXCR6 expression by NKT cells, is considered a survival and maturation factor for patrolling hepatic NKT cells.21Geissmann F. Cameron T.O. Sidobre S. et al.Intravascular immune surveillance by CXCR6+ NKT cells patrolling liver sinusoids.PLoS Biol. 2005; 3: e113Crossref PubMed Scopus (472) Google Scholar Early after injury, hepatic macrophages express high levels of CXCL16, thereby promoting the rapid intrahepatic accumulation of NKT cells at sites of tissue damage. Functionally, the CXCL16/CXCR6-mediated accumulation of NKT cells appears to be an important mechanism to amplify inflammatory signals early in the course of inflammation.22Wehr A. Baeck C. Heymann F. et al.Chemokine receptor CXCR6-dependent hepatic NK T Cell accumulation promotes inflammation and liver fibrosis.J Immunol. 2013; 190: 5226-5236Crossref PubMed Scopus (149) Google Scholar More recently, an unconventional T-cell subset at the edge between innate and adaptive immunity, the γδ T-cell receptor–expressing T cells (γδ T cells), has gained attention. Injured hepatocytes and cholangiocytes release high levels of CCL20, which attracts not only CCR6-expressing T-helper cell subsets23Oo Y.H. Banz V. Kavanagh D. et al.CXCR3-dependent recruitment and CCR6-mediated positioning of Th-17 cells in the inflamed liver.J Hepatol. 2012; 57: 1044-1051Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar but also the subset of γδ T cells expressing CCR6.24Hammerich L. Bangen J.M. Govaere O. et al.Chemokine receptor CCR6-dependent accumulation of gammadelta T cells in injured liver restricts hepatic inflammation and fibrosis.Hepatology. 2014; 59: 630-642Crossref PubMed Scopus (106) Google Scholar Fascinatingly, γδ T cells may have protective as well as pathogenic functions in liver diseases. Interferon (IFN)-γ–producing γδ T cells, for example, induce apoptosis in hepatocytes but also in hepatic tumor cells,25Ajuebor M.N. Jin Y. Gremillion G.L. et al.GammadeltaT cells initiate acute inflammation and injury in adenovirus-infected liver via cytokine-chemokine cross talk.J Virol. 2008; 82: 9564-9576Crossref PubMed Scopus (29) Google Scholar while IL-17/IL-22–expressing, CCR6+ γδ T cells can down-regulate the pathogenic effector functions of other immune cells and can promote apoptosis of fibrogenic stellate cells.24Hammerich L. Bangen J.M. Govaere O. et al.Chemokine receptor CCR6-dependent accumulation of gammadelta T cells in injured liver restricts hepatic inflammation and fibrosis.Hepatology. 2014; 59: 630-642Crossref PubMed Scopus (106) Google Scholar Although innate immune reactions dominate in the liver during the initial response to injury, adaptive immune cells, namely B and T lymphocytes, are vitally involved in the pathogenesis of hepatic inflammation during conditions of chronic liver damage. For instance, CD8+ cytotoxic T and CD4+ T-helper cells play important roles in hepatocellular damage, antiviral defense (to hepatitis viruses), or autoimmunity.18Racanelli V. Rehermann B. The liver as an immunological organ.Hepatology. 2006; 43: S54-S62Crossref PubMed Scopus (792) Google Scholar, 26Rehermann B. Pathogenesis of chronic viral hepatitis: differential roles of T cells and NK cells.Nat Med. 2013; 19: 859-868Crossref PubMed Scopus (328) Google Scholar CD4+ T-helper cells are subdivided into Th1, Th2, Th17, and regulatory (Treg) subsets based on expression of transcription factors and cytokines as well as functional properties.27Hammerich L. Heymann F. Tacke F. Role of IL-17 and Th17 cells in liver diseases.Clin Dev Immunol. 2011; 2011: 345803Crossref PubMed Scopus (186) Google Scholar CXCR3 and its signature ligands CXCL9 (MIG), CXCL10 (IP-10), and CXCL11 (I-TAC) could be convincingly linked to Th1 immune responses in the liver. These chemokines are inducible by IFN-γ and widely expressed by a vast number of hepatic parenchymal and nonparenchymal cells (hepatocytes, endothelial cells, cholangiocytes, HSCs, immune cells).7Wasmuth H.E. Tacke F. Trautwein C. Chemokines in liver inflammation and fibrosis.Semin Liver Dis. 2010; 30: 215-225Crossref PubMed Scopus (124) Google Scholar In particular, activated liver myofibroblasts release a variety of chemokines (including CCL2, CCL3, CCL5, CXCL8, CXCL9, and CXCL10) with an overall chemotactic activity for lymphocytes.28Holt A.P. Haughton E.L. Lalor P.F. et al.Liver myofibroblasts regulate infiltration and positioning of lymphocytes in human liver.Gastroenterology. 2009; 136: 705-714Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar CXCR3 mediates endothelial transmigration and T-cell chemotaxis to the liver lobule and thereby contributes to the expansion of liver inflammation to the parenchyma.5Oo Y.H. Shetty S. Adams D.H. The role of chemokines in the recruitment of lymphocytes to the liver.Dig Dis. 2010; 28: 31-44Crossref PubMed Scopus (94) Google Scholar Liver-infiltrating Th1 T cells also express CCR1 and in particular CCR5, which implicates interactions with CCL5 (RANTES), CCL3 (MIP-1α), and CCL4 (MIP-1β).5Oo Y.H. Shetty S. Adams D.H. The role of chemokines in the recruitment of lymphocytes to the liver.Dig Dis. 2010; 28: 31-44Crossref PubMed Scopus (94) Google Scholar Interfering with these chemokine pathways appears especially attractive in chronic viral hepatitis or autoimmune liver diseases, in which T cell–mediated cytotoxicity is crucial for immune pathogenesis. Although inflammation is observed in the majority of conditions associated with chronic damage, the functional role of specific chemokines and their cognate receptors differs between distinct entities of liver diseases. In this section, we briefly review the evidence, obtained in experimental and human studies, indicating the role of the chemokine system in the most common conditions of chronic liver injury and in primary liver cancer. Chemokines have received great attention in viral hepatitis, especially in chronic hepatitis C virus (HCV) infection. On the one hand, chemokines are involved in orchestrating the inflammatory response during disease progression in the liver, influencing the development of fibrosis and cirrhosis (discussed in the following text). On the other hand, chemokines are specifically involved in anti-HCV–directed adaptive immune responses that determine the maintenance or resolution of viral infection; furthermore, HCV itself can modulate chemokine and receptor expression, thereby aiding to escape efficient immune responses.29Fahey S. Dempsey E. Long A. The role of chemokines in acute and chronic hepatitis C infection.Cell Mol Immunol. 2014; 11: 25-40Crossref PubMed Scopus (0) Google Scholar Analyses of adaptive immune responses in HCV-infected patients and experimentally infected chimpanzees revealed that strong CD4+ Th1 helper and CD8+ effector T-cell responses are characteristic for successfully resolving HCV infection, while virus-specific T-cell responses are down-regulated during chronic infection and regulatory T cells increase.26Rehermann B. Pathogenesis of chronic viral hepatitis: differential roles of T cells and NK cells.Nat Med. 2013; 19: 859-868Crossref PubMed Scopus (328) Google Scholar Analyses of human liver samples from patients with HCV infection showed that chemokines are linked to the positioning of distinct immune cells within the microanatomy of the liver. CXCR3 appears to be important for various T-helper cell subsets, mainly Th1 and Th17 cells, which respond to CXCL9–11 released by sinusoidal endothelial cells and hepatocytes in HCV-infected livers.23Oo Y.H. Banz V. Kavanagh D. et al.CXCR3-dependent recruitment and CCR6-mediated positioning of Th-17 cells in the inflamed liver.J Hepatol. 2012; 57: 1044-1051Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar, 30Nguyen N. de Esch C. Cameron B. et al.Positioning of leukocyte subsets in the portal and lobular compartments of hepatitis C virus-infected liver correlates with local chemokine expression.J Gastroenterol Hepatol. 2014; 29: 860-869Crossref PubMed Scopus (0) Google Scholar, 31Butera D. Marukian S. Iwamaye A.E. et al.Plasma chemokine levels correlate with the outcome of antiviral therapy in patients with hepatitis C.Blood. 2005; 106: 1175-1182Crossref PubMed Scopus (163) Google Scholar CCR5 ligands (CCL3, CCL4, CCL5) are also up-regulated in livers of patients with hepatitis C, predominantly in the portal tracts, and mainly associated with cytotoxic CD8+ T cells30Nguyen N. de Esch C. Cameron B. et al.Positioning of leukocyte subsets in the portal and lobular compartments of hepatitis C virus-infected liver correlates with local chemokine expression.J Gastroenterol Hepatol. 2014; 29: 860-869Crossref PubMed Scopus (0) Google Scholar, 32Larrubia J.R. Calvino M. Benito S. et al.The role of CCR5/CXCR3 expressing CD8+ cells in liver damage and viral control during persistent hepatitis C virus infection.J Hepatol. 2007; 47: 632-641Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar and Th1-type immune responses.33Katsounas A. Schlaak J.F. Lempicki R.A. CCL5: a double-edged sword in host defense against the hepatitis C virus.Int Rev Immunol. 2011; 30: 366-378Crossref PubMed Scopus (0) Google Scholar Interestingly, the CCR5 gene is subject to various mutations, including a 32–base pair deletion resulting in a frame shift (CCR5Δ32). However, to what extent this functional CCR5 deficiency alters the natural course of infection or response to treatment in HCV-infected subjects remains controversial.34Coenen M. Nattermann J. The role of CCR5 in HCV infection.Eur J Med Res. 2010; 15: 97-101Crossref PubMed Google Scholar Cytotoxic T cells may also respond to increased CCL19 and CCL21 expression via chemokine receptor CCR735Bonacchi A. Petrai I. Defranco R.M. et al.The chemokine CCL21 modulates lymphocyte recruitment and fibrosis in chronic hepatitis C.Gastroenterology. 2003; 125: 1060-1076Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar; moreover, CCR7 is critical for the migration of dendritic cells from inflamed liver to the draining lymph nodes.36Jiao J. Sastre D. Fiel M.I. et al.Dendritic cell regulation of carbon tetrachloride-induced murine liver fibrosis regression.Hepatology. 2012; 55: 244-255Crossref PubMed Scopus (100) Google Scholar CXCL13 expression is correlated with accumulation of CXCR5+ B cells.30Nguyen N. de Esch C. Cameron B. et al.Positioning of leukocyte subsets in the portal and lobular compartments of hepatitis C virus-infected liver correlates with local chemokine expression.J Gastroenterol Hepatol. 2014; 29: 860-869Crossref PubMed Scopus (0) Google Scholar Mechanistically, HCV core and NS5A proteins have been shown to affect CCL5 secretion by modulating CCL5 promoter activity,33Katsounas A. Schlaak J.F. Lempicki R.A. CCL5: a double-edged sword in host defense against the hepatitis C virus.Int Rev Immunol. 2011; 30: 366-378Crossref PubMed Scopus (0) Google Scholar, 37Soo H.M. Garzino-Demo A. Hong W. et al.Expression of a full-length hepatitis C virus cDNA up-regulates the expression of CC chemokines MCP-1 and RANTES.Virology. 2002; 303: 253-277Crossref PubMed Scopus (0) Google Scholar and HCV double-stranded RNA intermediates were shown to induce the expression of CXCR3 and CCR5 ligands in infected hepatocytes. These chemokines, namely CXCL9–11 and CCL3–5, are significantly increased in the serum and livers of patients or HCV-infected chimpanzees roughly within 1 month after acute HCV infection.38Zeremski M. Hooker G. Shu M.A. et al.Induction of CXCR3- and CCR5-associated chemokines during acute hepatitis C virus infection.J Hepatol. 2011; 55: 545-553Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, 39Shin E.C. Park S.H. Demino M. et al.Delayed induction, not impaired recruitment, of specific CD8(+) T cells causes the late onset of acute hepatitis C.Gastroenterology. 2011; 141 (695 e1): 686-695Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar In addition, HCV-infected hepatocytes can induce the expression of the chemokines CCL17 and CCL22 in neighboring dendritic cells, which promotes the recruitment of immunosuppressive regulatory T cells via CCR4.40Riezu-Boj J.I. Larrea E. Aldabe R. et al.Hepatitis C virus induces the expression of CCL17 and CCL22 chemokines that attract regulatory T cells to the site of infection.J Hepatol. 2011; 54: 422-431Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 41Oo Y.H. Weston C.J. Lalor P.F. et al.Distinct roles for CCR4 and CXCR3 in the recruitment and positioning of regulatory T cells in the inflamed human liver.J Immunol. 2010; 184: 2886-2898Crossref PubMed Scopus (164) Google Scholar Among the various chemokines up-regulated in HCV-infected patients, CXCL10 might hold remarkable potential as a biomarker. It has recently been shown that CXCL10 expression correlates with the degree of apoptosis in patients with hepatitis C and that this action is mediated by activation of the noncognate receptor TLR-4.42Sahin H. Borkham-Kamphorst E. do O N.T. et al.Proapoptotic effects of the chemokine, CXCL 10 are mediated by the noncognate receptor TLR4 in hepatocytes.Hepatology. 2013; 57: 797-805Crossref PubMed Scopus (0) Google Scholar Intrahepatic and even serum CXCL10 levels have been reproducibly associated with the extent of HCV-induced liver fibrosis.43Zeremski M. Dimova R. Brown Q. et al.Peripheral CXCR3-associated chemokines as biomarkers of fibrosis in chronic hepatitis C virus infection.J Infect Dis. 2009; 200: 1774-1780Crossref PubMed Scopus (94) Google Scholar, 44Zeremski M. Petrovic L.M. Chiriboga L. et al.Intrahepatic levels of CXCR3-associated chemokines correlate with liver inflammation and fibrosis in chronic hepatitis C.Hepatology. 2008; 48: 1440-1450Crossref PubMed Scopus (179) Google Scholar, 45Romero A.I. Lagging M. Westin J. et al.Interferon (IFN)-gamma-inducible protein-10: asso