Chemokines in Liver Inflammation and Fibrosis

ABSTRACT

Chemokines are a class of small chemotactic molecules with cytokine-like functions, which are well known to orchestrate inflammatory responses within different organs. Overall, more than 50 ligands and 19 receptors belong to the network. In recent years, accumulating functional and genetic evidence suggests that chemokines play a critical role in acute and chronic liver diseases, mediating the infiltration of immune cells (monocytes, T-cells) into the injured liver along a concentration gradient. However, chemokines can also directly affect the biology of liver resident cells, such as hepatic stellate cells and hepatocytes during inflammatory and fibrogenic tissue responses. Although the chemokine system has long been considered highly redundant, studies in knockout animals have convincingly demonstrated that single chemokines and chemokine receptors strongly affect the phenotype of toxic and inflammatory liver disease in vivo. However, depending on the model, these effects can be harmful (proinflammatory, profibrogenic) or beneficial (antifibrotic). This aspect of chemokine biology must be understood before these molecules and their receptors are targeted for therapeutic purposes. Here, we summarize current knowledge on the genetic and functional importance of the chemokine network in injury and highlight their potential for intervening in the inflammation and fibrosis that drives liver disease progression.

KEYWORDS

Chemokines - liver fibrosis - genetics - leukocyte recruitment - stellate cell activation

REFERENCES

• 1 Charo I F, Ransohoff R M. The many roles of chemokines and chemokine receptors in inflammation.  N Engl J Med. 2006;  354 610-621
• 2 Luster A D. Chemokines—chemotactic cytokines that mediate inflammation.  N Engl J Med. 1998;  338 436-445
• 3 Mantovani A. The chemokine system: redundancy for robust outputs.  Immunol Today. 1999;  20 254-257
• 4 Bonecchi R, Galliera E, Borroni E M, Corsi M M, Locati M, Mantovani A. Chemokines and chemokine receptors: an overview.  Front Biosci. 2009;  14 540-551
• 5 Rot A, von Andrian U H. Chemokines in innate and adaptive host defense: basic chemokinese grammar for immune cells.  Annu Rev Immunol. 2004;  22 891-928
• 6 Murphy P M, Baggiolini M, Charo I F et al.. International union of pharmacology. XXII. Nomenclature for chemokine receptors.  Pharmacol Rev. 2000;  52 145-176
• 7 Thelen M. Dancing to the tune of chemokines.  Nat Immunol. 2001;  2 129-134
• 8 Graham G J. D6 and the atypical chemokine receptor family: novel regulators of immune and inflammatory processes.  Eur J Immunol. 2009;  39 342-351
• 9 Mantovani A, Bonecchi R, Locati M. Tuning inflammation and immunity by chemokine sequestration: decoys and more.  Nat Rev Immunol. 2006;  6 907-918
• 10 Mantovani A, Locati M, Vecchi A, Sozzani S, Allavena P. Decoy receptors: a strategy to regulate inflammatory cytokines and chemokines.  Trends Immunol. 2001;  22 328-336
• 11 Jamieson T, Cook D N, Nibbs R J et al.. The chemokine receptor D6 limits the inflammatory response in vivo.  Nat Immunol. 2005;  6 403-411
• 12 Martinez de la Torre Y, Buracchi C, Borroni E M et al.. Protection against inflammation- and autoantibody-caused fetal loss by the chemokine decoy receptor D6.  Proc Natl Acad Sci U S A. 2007;  104 2319-2324
• 13 Whitehead G S, Wang T, DeGraff L M et al.. The chemokine receptor D6 has opposing effects on allergic inflammation and airway reactivity.  Am J Respir Crit Care Med. 2007;  175 243-249
• 14 Berres M L, Trautwein C, Zaldivar M M et al.. The chemokine scavenging receptor D6 limits acute toxic liver injury in vivo.  Biol Chem. 2009;  390 1039-1045
• 15 Pease J E, Horuk R. Chemokine receptor antagonists: part 1.  Expert Opin Ther Pat. 2009;  19 39-58
• 16 Pease J E, Horuk R. Chemokine receptor antagonists: part 2.  Expert Opin Ther Pat. 2009;  19 199-221
• 17 Sayana S, Khanlou H. Maraviroc: a new CCR5 antagonist.  Expert Rev Anti Infect Ther. 2009;  7 9-19
• 18 Frazer K A, Murray S S, Schork N J, Topol E J. Human genetic variation and its contribution to complex traits.  Nat Rev Genet. 2009;  10 241-251
• 19 Hellerbrand C, Wasmuth H E. Genomewide genetic association studies in hepatology: the end of searching for the needle in the haystack?.  Hepatology. 2007;  46 1661-1663
• 20 Osterreicher C H, Stickel F, Brenner D A. Genomics of liver fibrosis and cirrhosis.  Semin Liver Dis. 2007;  27 28-43
• 21 Woitas R P, Ahlenstiel G, Iwan A et al.. Frequency of the HIV-protective CC chemokine receptor 5-Delta32/Delta32 genotype is increased in hepatitis C.  Gastroenterology. 2002;  122 1721-1728
• 22 Arenzana-Seisdedos F, Parmentier M. Genetics of resistance to HIV infection: role of co-receptors and co-receptor ligands.  Semin Immunol. 2006;  18 387-403
• 23 Wasmuth H E, Werth A, Mueller T et al.. CC chemokine receptor 5 delta32 polymorphism in two independent cohorts of hepatitis C virus infected patients without hemophilia.  J Mol Med. 2004;  82 64-69
• 24 Promrat K, McDermott D H, Gonzalez C M et al.. Associations of chemokine system polymorphisms with clinical outcomes and treatment responses of chronic hepatitis C.  Gastroenterology. 2003;  124 352-360
• 25 Hellier S, Frodsham A J, Hennig B J et al.. Association of genetic variants of the chemokine receptor CCR5 and its ligands, RANTES and MCP-2, with outcome of HCV infection.  Hepatology. 2003;  38 1468-1476
• 26 Goulding C, McManus R, Murphy A et al.. The CCR5-delta32 mutation: impact on disease outcome in individuals with hepatitis C infection from a single source.  Gut. 2005;  54 1157-1161
• 27 Wasmuth H E, Matern S, Lammert F. From genotypes to haplotypes in hepatobiliary diseases: one plus one equals (sometimes) more than two.  Hepatology. 2004;  39 604-607
• 28 Wasmuth H E, Werth A, Mueller T et al.. Haplotype-tagging RANTES gene variants influence response to antiviral therapy in chronic hepatitis C.  Hepatology. 2004;  40 327-334
• 29 Frazer K A, Ballinger D G, Cox D R International HapMap Consortium et al. A second generation human haplotype map of over 3.1 million SNPs.  Nature. 2007;  449 851-861
• 30 Wiederholt T, von Westernhagen M, Zaldivar M M et al.. Genetic variations of the chemokine scavenger receptor D6 are associated with liver inflammation in chronic hepatitis C.  Hum Immunol. 2008;  69 861-866
• 31 Mühlbauer M, Bosserhoff A K, Hartmann A et al.. A novel MCP-1 gene polymorphism is associated with hepatic MCP-1 expression and severity of HCV-related liver disease.  Gastroenterology. 2003;  125 1085-1093
• 32 Wasmuth H E, Zaldivar M M, Berres M L et al.. The fractalkine receptor CX3CR1 is involved in liver fibrosis due to chronic hepatitis C infection.  J Hepatol. 2008;  48 208-215
• 33 Deng G, Zhou G, Zhang R et al.. Regulatory polymorphisms in the promoter of CXCL10 gene and disease progression in male hepatitis B virus carriers.  Gastroenterology. 2008;  134 716-726
• 34 Weiskirchen R, Wasmuth H E. The genes that underlie fatty liver disease: the harvest has begun.  Hepatology. 2009;  49 692-694
• 35 Hillebrandt S, Goos C, Matern S, Lammert F. Genome-wide analysis of hepatic fibrosis in inbred mice identifies the susceptibility locus Hfib1 on chromosome 15.  Gastroenterology. 2002;  123 2041-2051
• 36 Hillebrandt S, Wasmuth H E, Weiskirchen R et al.. Complement factor 5 is a quantitative trait gene that modifies liver fibrogenesis in mice and humans.  Nat Genet. 2005;  37 835-843
• 37 Wasmuth H E, Lammert F, Zaldivar M M et al.. Antifibrotic effects of CXCL9 and its receptor CXCR3 in livers of mice and humans.  Gastroenterology. 2009;  137 309-319
• 38 Abiola O, Angel J M, Avner P Complex Trait Consortium et al. The nature and identification of quantitative trait loci: a community's view.  Nat Rev Genet. 2003;  4 911-916
• 39 Ramm G A, Shepherd R W, Hoskins A C et al.. Fibrogenesis in pediatric cholestatic liver disease: role of taurocholate and hepatocyte-derived monocyte chemotaxis protein-1 in hepatic stellate cell recruitment.  Hepatology. 2009;  49 533-544
• 40 Kruglov E A, Nathanson R A, Nguyen T, Dranoff J A. Secretion of MCP-1/CCL2 by bile duct epithelia induces myofibroblastic transdifferentiation of portal fibroblasts.  Am J Physiol Gastrointest Liver Physiol. 2006;  290 G765-G771
• 41 Marra F, Valente A J, Pinzani M, Abboud H E. Cultured human liver fat-storing cells produce monocyte chemotactic protein-1. Regulation by proinflammatory cytokines.  J Clin Invest. 1993;  92 1674-1680
• 42 Marra F, Grandaliano G, Valente A J, Abboud H E. Thrombin stimulates proliferation of liver fat-storing cells and expression of monocyte chemotactic protein-1: potential role in liver injury.  Hepatology. 1995;  22 780-787
• 43 Holt A P, Salmon M, Buckley C D, Adams D H. Immune interactions in hepatic fibrosis.  Clin Liver Dis. 2008;  12 861-882 x
• 44 Holt A P, Haughton E L, Lalor P F, Filer A, Buckley C D, Adams D H. Liver myofibroblasts regulate infiltration and positioning of lymphocytes in human liver.  Gastroenterology. 2009;  136 705-714
• 45 Seki E, de Minicis S, Inokuchi S et al.. CCR2 promotes hepatic fibrosis in mice.  Hepatology. 2009;  50 185-197
• 46 Karlmark 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;  50 261-274
• 47 Zamara E, Galastri S, Aleffi S et al.. Prevention of severe toxic liver injury and oxidative stress in MCP-1-deficient mice.  J Hepatol. 2007;  46 230-238
• 48 Kanda H, Tateya S, Tamori Y et al.. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity.  J Clin Invest. 2006;  116 1494-1505
• 49 Tamura Y, Sugimoto M, Murayama T et al.. Inhibition of CCR2 ameliorates insulin resistance and hepatic steatosis in db/db mice.  Arterioscler Thromb Vasc Biol. 2008;  28 2195-2201
• 50 Weisberg S P, Hunter D, Huber R et al.. CCR2 modulates inflammatory and metabolic effects of high-fat feeding.  J Clin Invest. 2006;  116 115-124
• 51 Nischalke H D, Nattermann J, Fischer H P, Sauerbruch T, Spengler U, Dumoulin F L. Semiquantitative analysis of intrahepatic CC-chemokine mRNas in chronic hepatitis C.  Mediators Inflamm. 2004;  13 357-359
• 52 Seki E, De Minicis S, Gwak G Y et al.. CCR1 and CCR5 promote hepatic fibrosis in mice.  J Clin Invest. 2009;  119 1858-1870
• 53 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. 2003;  285 G949-G958
• 54 De Minicis S, Seki E, Uchinami H et al.. Gene expression profiles during hepatic stellate cell activation in culture and in vivo.  Gastroenterology. 2007;  132 1937-1946
• 55 Ruddell R G, Knight B, Tirnitz-Parker J E et al.. Lymphotoxin-beta receptor signaling regulates hepatic stellate cell function and wound healing in a murine model of chronic liver injury.  Hepatology. 2009;  49 227-239
• 56 Ajuebor M N, Aspinall A I, Zhou F et al.. Lack of chemokine receptor CCR5 promotes murine fulminant liver failure by preventing the apoptosis of activated CD1d-restricted NKT cells.  J Immunol. 2005;  174 8027-8037
• 57 Ajuebor M N, Wondimu Z, Hogaboam C M, Le T, Proudfoot A E, Swain M G. 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 1975-1988
• 58 McKimmie C S, Fraser A R, Hansell C et al.. Hemopoietic cell expression of the chemokine decoy receptor D6 is dynamic and regulated by GATA1.  J Immunol. 2008;  181 3353-3363
• 59 Bonacchi A, Petrai I, Defranco R M et al.. The chemokine CCL21 modulates lymphocyte recruitment and fibrosis in chronic hepatitis C.  Gastroenterology. 2003;  125 1060-1076
• 60 Gunn M D, Kyuwa S, Tam C et al.. Mice lacking expression of secondary lymphoid organ chemokine have defects in lymphocyte homing and dendritic cell localization.  J Exp Med. 1999;  189 451-460
• 61 Connolly M K, Bedrosian A S, Mallen-St Clair J et al.. In liver fibrosis, dendritic cells govern hepatic inflammation in mice via TNF-alpha.  J Clin Invest. 2009;  119 3213-3225
• 62 Baggiolini M. Chemokines in pathology and medicine.  J Intern Med. 2001;  250 91-104
• 63 Asselah T, Bièche I, Laurendeau I et al.. Liver gene expression signature of mild fibrosis in patients with chronic hepatitis C.  Gastroenterology. 2005;  129 2064-2075
• 64 Ryseck R P, MacDonald-Bravo H, Mattei M G, Bravo R. Cloning and sequence of a secretory protein induced by growth factors in mouse fibroblasts.  Exp Cell Res. 1989;  180 266-275
• 65 Strieter R M, Belperio J A, Phillips R J, Keane M P. CXC chemokines in angiogenesis of cancer.  Semin Cancer Biol. 2004;  14 195-200
• 66 Heydtmann M, Adams D H. Chemokines in the immunopathogenesis of hepatitis C infection.  Hepatology. 2009;  49 676-688
• 67 Zeremski 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 1440-1450
• 68 Zeremski M, Dimova R, Brown Q, Jacobson I M, Markatou M, Talal A H. Peripheral CXCR3-associated chemokines as biomarkers of fibrosis in chronic hepatitis C virus infection.  J Infect Dis. 2009;  200 1774-1780
• 69 Helbig K J, Ruszkiewicz A, Lanford R E et al.. Differential expression of the CXCR3 ligands in chronic hepatitis C virus (HCV) infection and their modulation by HCV in vitro.  J Virol. 2009;  83 836-846
• 70 Santodomingo-Garzon T, Han J, Le T, Yang Y, Swain M G. Natural killer T cells regulate the homing of chemokine CXC receptor 3-positive regulatory T cells to the liver in mice.  Hepatology. 2009;  49 1267-1276
• 71 Rosenblum J M, Zhang Q W, Siu G et al.. CXCR3 antagonism impairs the development of donor-reactive, IFN-gamma-producing effectors and prolongs allograft survival.  Transplantation. 2009;  87 360-369
• 72 Barbi J, Oghumu S, Rosas L E et al.. Lack of CXCR3 delays the development of hepatic inflammation but does not impair resistance to Leishmania donovani.  J Infect Dis. 2007;  195 1713-1717
• 73 Wynn T A. Fibrotic disease and the T(H)1/T(H)2 paradigm.  Nat Rev Immunol. 2004;  4 583-594
• 74 Shi Z, Wakil A E, Rockey D C. Strain-specific differences in mouse hepatic wound healing are mediated by divergent T helper cytokine responses.  Proc Natl Acad Sci U S A. 1997;  94 10663-10668
• 75 Li Z, Soloski M J, Diehl A M. Dietary factors alter hepatic innate immune system in mice with nonalcoholic fatty liver disease.  Hepatology. 2005;  42 880-885
• 76 Bonacchi A, Romagnani P, Romanelli R G et al.. Signal transduction by the chemokine receptor CXCR3: activation of Ras/ERK, Src, and phosphatidylinositol 3-kinase/Akt controls cell migration and proliferation in human vascular pericytes.  J Biol Chem. 2001;  276 9945-9954
• 77 Lasagni L, Francalanci M, Annunziato F 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. 2003;  197 1537-1549
• 78 Datta D, Flaxenburg J A, Laxmanan S et al.. Ras-induced modulation of CXCL10 and its receptor splice variant CXCR3-B in MDA-MB-435 and MCF-7 cells: relevance for the development of human breast cancer.  Cancer Res. 2006;  66 9509-9518
• 79 von Hundelshausen P, Petersen F, Brandt E. Platelet-derived chemokines in vascular biology.  Thromb Haemost. 2007;  97 704-713
• 80 Schaffner A, Rhyn P, Schoedon G, Schaer D J. Regulated expression of platelet factor 4 in human monocytes—role of PARs as a quantitatively important monocyte activation pathway.  J Leukoc Biol. 2005;  78 202-209
• 81 Lasagni L, Grepin R, Mazzinghi B et al.. PF-4/CXCL4 and CXCL4L1 exhibit distinct subcellular localization and a differentially regulated mechanism of secretion.  Blood. 2007;  109 4127-4134
• 82 Iannacone M, Sitia G, Isogawa M et al.. Platelets mediate cytotoxic T lymphocyte-induced liver damage.  Nat Med. 2005;  11 1167-1169
• 83 Lang P A, Contaldo C, Georgiev P et al.. Aggravation of viral hepatitis by platelet-derived serotonin.  Nat Med. 2008;  14 756-761
• 84 Zaldivar M M, Pauels K, Von Hundelshausen P et al.. CXC chemokine ligand 4 (Cxc14) is a platelet-derived mediator of experimental liver fibrosis.  Hepatology. 2010;  51 1345-1353
• 85 Weber C, Koenen R R. Fine-tuning leukocyte responses: towards a chemokine “interactome.”  Trends Immunol. 2006;  27 268-273
• 86 von Hundelshausen P, Koenen R R, Sack M et al.. Heterophilic interactions of platelet factor 4 and RANTES promote monocyte arrest on endothelium.  Blood. 2005;  105 924-930
• 87 Koenen R R, von Hundelshausen P, Nesmelova I V et al.. Disrupting functional interactions between platelet chemokines inhibits atherosclerosis in hyperlipidemic mice.  Nat Med. 2009;  15 97-103
• 88 Wald O, Pappo O, Safadi R et al.. Involvement of the CXCL12/CXCR4 pathway in the advanced liver disease that is associated with hepatitis C virus or hepatitis B virus.  Eur J Immunol. 2004;  34 1164-1174
• 89 Schrage A, Wechsung K, Neumann K et al.. Enhanced T cell transmigration across the murine liver sinusoidal endothelium is mediated by transcytosis and surface presentation of chemokines.  Hepatology. 2008;  48 1262-1272
• 90 Hong F, Tuyama A, Lee T F et al.. Hepatic stellate cells express functional CXCR4: role in stromal cell-derived factor-1alpha-mediated stellate cell activation.  Hepatology. 2009;  49 2055-2067
• 91 von Vietinghoff S, Ley K. Homeostatic regulation of blood neutrophil counts.  J Immunol. 2008;  181 5183-5188
• 92 Burger J A, Peled A. CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers.  Leukemia. 2009;  23 43-52
• 93 Omenetti A, Syn W K, Jung Y et al.. Repair-related activation of hedgehog signaling promotes cholangiocyte chemokine production.  Hepatology. 2009;  50 518-527
• 94 Omenetti A, Porrello A, Jung Y et al.. Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans.  J Clin Invest. 2008;  118 3331-3342
• 95 Ludwig A, Weber C. Transmembrane chemokines: versatile “special agents” in vascular inflammation.  Thromb Haemost. 2007;  97 694-703
• 96 Tacke F, Alvarez D, Kaplan T J et al.. Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques.  J Clin Invest. 2007;  117 185-194
• 97 Efsen E, Grappone C, DeFranco R M et al.. Up-regulated expression of fractalkine and its receptor CX3CR1 during liver injury in humans.  J Hepatol. 2002;  37 39-47
• 98 Isse K, Harada K, Zen Y et al.. Fractalkine and CX3CR1 are involved in the recruitment of intraepithelial lymphocytes of intrahepatic bile ducts.  Hepatology. 2005;  41 506-516
• 99 Shimoda S, Harada K, Niiro H et al.. CX3CL1 (fractalkine): a signpost for biliary inflammation in primary biliary cirrhosis.  Hepatology. 2010;  51 567-575
• 100 Karlmark K R, Wasmuth H E, Trautwein C, Tacke F. Chemokine-directed immune cell infiltration in acute and chronic liver disease.  Expert Rev Gastroenterol Hepatol. 2008;  2 233-242
• 101 Marra F.. Chemokines in liver inflammation and fibrosis.  Front Biosci. 2002;  7 d1899-1914