Current Pathobiology Reports

, Volume 3, Issue 4, pp 283–290 | Cite as

The Roles of CXCL16 and CXCR6 in Liver Inflammation and Fibrosis

  • Alexander Wehr
  • Frank Tacke
Cytokines That Affect Liver Fibrosis and Activation of Hepatic Myofibroblasts (Tatiana Kisseleva, Section Editor)
Part of the following topical collections:
  1. Cytokines That Affect Liver Fibrosis and Activation of Hepatic Myofibroblasts


Chemokines and their receptors are key mediators in regulating liver inflammation by controlling the intrahepatic accumulation of immune cells and affecting stress responses of parenchymal or nonparenchymal liver cells to injury. Experimental evidence from human patients and mouse models revealed that the chemokine CXCL16 and its receptor CXCR6 regulate several pathways in liver diseases. The CXCR6–CXCL16-mediated lymphocyte recruitment, especially of NKT cells, is critical for the initiation of hepatic and biliary inflammation and for the progression to liver fibrosis. Targeting this pathway may hold promising therapeutic potential, e.g., in nonalcoholic steatohepatitis. The involvement of CXCR6–CXCL16 with hepatocarcinogenesis appears to be more complex, and potentially counteracting functions with respect to cancer invasiveness, angiogenesis, and antitumoral NKT cell activities are discussed. Further studies are needed to explore the exact pathomechanisms of this pathway in the progression of liver diseases and evaluate its potential as a biomarker and therapeutic target.


CXCR6 CXCL16 Liver cirrhosis HCC Liver cancer 



This work was supported by the German Research Foundation (DFG Ta434/3–1 and SFB/TRR57) and by the Interdisciplinary Center for Clinical Research (IZKF) Aachen. The authors gratefully acknowledge the expert discussions with all members of the Tacke lab.


Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Bataller R, Brenner DA (2005) Liver fibrosis. J Clin Investig 115(2):209–218PubMedCentralCrossRefPubMedGoogle Scholar
  2. 2.
    • Marra F, Tacke F (2014) Roles for chemokines in liver disease. Gastroenterology. 147(3):577e1–494 e1. A comprehensive review discussing the roles of chemokines in different liver diseases Google Scholar
  3. 3.
    Charo IF, Ransohoff RM (2006) The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med 354(6):610–621CrossRefPubMedGoogle Scholar
  4. 4.
    Zimmermann HW, Tacke F (2011) Modification of chemokine pathways and immune cell infiltration as a novel therapeutic approach in liver inflammation and fibrosis. Inflamm Allergy Drug Targets 10(6):509–536CrossRefPubMedGoogle Scholar
  5. 5.
    Alkhatib G, Liao F, Berger EA, Farber JM, Peden KW (1997) A new SIV co-receptor, STRL33. Nature 388(6639):238CrossRefPubMedGoogle Scholar
  6. 6.
    Liao F, Alkhatib G, Peden KW, Sharma G, Berger EA, Farber JM (1997) STRL33, A novel chemokine receptor-like protein, functions as a fusion cofactor for both macrophage-tropic and T cell line-tropic HIV-1. J Exp Med 185(11):2015–2023PubMedCentralCrossRefPubMedGoogle Scholar
  7. 7.
    Tuncer C, Oo YH, Murphy N, Adams DH, Lalor PF (2013) The regulation of T-cell recruitment to the human liver during acute liver failure. Liver Int 33(6):852–863CrossRefPubMedGoogle Scholar
  8. 8.
    • Wehr A, Baeck C, Heymann F, Niemietz PM, Hammerich L, Martin C, Zimmermann HW, Pack O, Gassler N, Hittatiya K, et al. Chemokine receptor CXCR6-dependent hepatic NK T cell accumulation promotes inflammation and liver fibrosis. J Immunol. 2013;190(10):5226–5536. This study revealed that NKT cells migrate dependent on CXCR6 into injured livers and exert a profibrotic function Google Scholar
  9. 9.
    Heydtmann M, Lalor PF, Eksteen JA, Hubscher SG, Briskin M, Adams DH (2005) CXC chemokine ligand 16 promotes integrin-mediated adhesion of liver-infiltrating lymphocytes to cholangiocytes and hepatocytes within the inflamed human liver. J immunol 174(2):1055–1062CrossRefPubMedGoogle Scholar
  10. 10.
    Gao Q, Zhao YJ, Wang XY, Qiu SJ, Shi YH, Sun J, Yi Y, Shi JY, Shi GM, Ding ZB et al (2012) CXCR6 upregulation contributes to a proinflammatory tumor microenvironment that drives metastasis and poor patient outcomes in hepatocellular carcinoma. Cancer Res 72(14):3546–3556CrossRefPubMedGoogle Scholar
  11. 11.
    Fairfax KC, Everts B, Smith AM, Pearce EJ (2013) Regulation of the development of the hepatic B cell compartment during Schistosoma mansoni infection. J Immunol 191(8):4202–4210CrossRefPubMedGoogle Scholar
  12. 12.
    Oo YH, Banz V, Kavanagh D, Liaskou E, Withers DR, Humphreys E, Reynolds GM, Lee-Turner L, Kalia N, Hubscher SG et al (2012) CXCR3-dependent recruitment and CCR6-mediated positioning of Th-17 cells in the inflamed liver. J Hepatol 57(5):1044–1051PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.
    Kim CH, Kunkel EJ, Boisvert J, Johnston B, Campbell JJ, Genovese MC, Greenberg HB, Butcher EC (2001) Bonzo/CXCR6 expression defines type 1-polarized T-cell subsets with extralymphoid tissue homing potential. J Clin Investig 107(5):595–601PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Johnston B, Kim CH, Soler D, Emoto M, Butcher EC (2003) Differential chemokine responses and homing patterns of murine TCR alpha beta NKT cell subsets. J Immunol 171(6):2960–2969CrossRefPubMedGoogle Scholar
  15. 15.
    Possot C, Schmutz S, Chea S, Boucontet L, Louise A, Cumano A, Golub R (2011) Notch signaling is necessary for adult, but not fetal, development of RORgammat(+) innate lymphoid cells. Nat Immunol 12(10):949–958CrossRefPubMedGoogle Scholar
  16. 16.
    Shimaoka T, Kume N, Minami M, Hayashida K, Kataoka H, Kita T, Yonehara S (2000) Molecular cloning of a novel scavenger receptor for oxidized low density lipoprotein, SR-PSOX, on macrophages. J Biol Chem 275(52):40663–40666CrossRefPubMedGoogle Scholar
  17. 17.
    • Hammad MA, Abdel-Bakky MS, Walker LA, and Ashfaq MK (2011) Oxidized low-density lipoprotein and tissue factor are involved in monocrotaline/lipopolysaccharide-induced hepatotoxicity. Arch Toxicol 85(9):1079–1089. This study was the first demonstration that CXCL16 is expressed on hepatocytes and serves as a scavenger receptor to internalize oxLDL, which then leads to severe liver damage Google Scholar
  18. 18.
    • Wehr A, Baeck C, Ulmer F, Gassler N, Hittatiya K, Luedde T, Neumann UP, Trautwein C, and Tacke F (2014) Pharmacological inhibition of the chemokine CXCL16 diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury. PloS One 9(11):e112327. A proof-of-concept study showing the efficacy of blocking CXCL16 in a mouse model of steatohepatitis Google Scholar
  19. 19.
    Matloubian M, David A, Engel S, Ryan JE, Cyster JG (2000) A transmembrane CXC chemokine is a ligand for HIV-coreceptor Bonzo. Nat Immunol 1(4):298–304CrossRefPubMedGoogle Scholar
  20. 20.
    • Geissmann F, Cameron TO, Sidobre S, Manlongat N, Kronenberg M, Briskin MJ, Dustin ML, Littman DR (2005) Intravascular immune surveillance by CXCR6 + NKT cells patrolling liver sinusoids. PLOS Biol. 3(4):e113. This study was the first demonstration that CXCR6 expressing NKT cells migrate into the liver and crawl along the liver sinosoidal endothelial cells, which highly express mbCXCL16 Google Scholar
  21. 21.
    Gough PJ, Garton KJ, Wille PT, Rychlewski M, Dempsey PJ, Raines EW (2004) A disintegrin and metalloproteinase 10-mediated cleavage and shedding regulates the cell surface expression of CXC chemokine ligand 16. J Immunol 172(6):3678–3685CrossRefPubMedGoogle Scholar
  22. 22.
    Schulte A, Schulz B, Andrzejewski MG, Hundhausen C, Mletzko S, Achilles J, Reiss K, Paliga K, Weber C, John SR et al (2007) Sequential processing of the transmembrane chemokines CX3CL1 and CXCL16 by alpha- and gamma-secretases. Biochem Biophys Res Commun 358(1):233–240CrossRefPubMedGoogle Scholar
  23. 23.
    Boisvert J, Kunkel EJ, Campbell JJ, Keeffe EB, Butcher EC, Greenberg HB (2003) Liver-infiltrating lymphocytes in end-stage hepatitis C virus: subsets, activation status, and chemokine receptor phenotypes. J Hepatol 38(1):67–75CrossRefPubMedGoogle Scholar
  24. 24.
    Wang J, Holmes TH, Cheung R, Greenberg HB, He XS (2004) Expression of chemokine receptors on intrahepatic and peripheral lymphocytes in chronic hepatitis C infection: its relationship to liver inflammation. J Infect Dis 190(5):989–997CrossRefPubMedGoogle Scholar
  25. 25.
    Northfield JW, Kasprowicz V, Lucas M, Kersting N, Bengsch B, Kim A, Phillips RE, Walker BD, Thimme R, Lauer G et al (2008) CD161 expression on hepatitis C virus-specific CD8 + T cells suggests a distinct pathway of T cell differentiation. Hepatology 47(2):396–406CrossRefPubMedGoogle Scholar
  26. 26.
    Sato T, Thorlacius H, Johnston B, Staton TL, Xiang W, Littman DR, Butcher EC (2005) Role for CXCR6 in recruitment of activated CD8 + lymphocytes to inflamed liver. J Immunol 174(1):277–283CrossRefPubMedGoogle Scholar
  27. 27.
    Monticelli LA, Yang Y, Knell J, D’Cruz LM, Cannarile MA, Engel I, Kronenberg M, Goldrath AW (2009) Transcriptional regulator Id2 controls survival of hepatic NKT cells. Proc Natl Acad Sci USA 106(46):19461–19466PubMedCentralCrossRefPubMedGoogle Scholar
  28. 28.
    Germanov E, Veinotte L, Cullen R, Chamberlain E, Butcher EC, Johnston B (2008) Critical role for the chemokine receptor CXCR6 in homeostasis and activation of CD1d-restricted NKT cells. J Immunol 181(1):81–91CrossRefPubMedGoogle Scholar
  29. 29.
    Bendelac A, Savage PB, Teyton L (2007) The biology of NKT cells. Annu Rev Immunol 25:297–336CrossRefPubMedGoogle Scholar
  30. 30.
    Bouazzaoui A, Spacenko E, Mueller G, Miklos S, Huber E, Holler E, Andreesen R, Hildebrandt GC (2009) Chemokine and chemokine receptor expression analysis in target organs of acute graft-versus-host disease. Genes Immun 10(8):687–701CrossRefPubMedGoogle Scholar
  31. 31.
    • Paust S, Gill HS, Wang BZ, Flynn MP, Moseman EA, Senman B, Szczepanik M, Telenti A, Askenase PW, Compans RW, et al. (2010) Critical role for the chemokine receptor CXCR6 in NK cell-mediated antigen-specific memory of haptens and viruses. Nat Immunol. 11(12):1127–1135. This study showed that NK cells can develop adaptive immune responses to structurally diverse antigens, which requires the expression of CXCR6 Google Scholar
  32. 32.
    Walzer T, Vivier E (2011) G-protein-coupled receptors in control of natural killer cell migration. Trends Immunol 32(10):486–492CrossRefPubMedGoogle Scholar
  33. 33.
    Majewska-Szczepanik M, Paust S, von Andrian UH, Askenase PW, Szczepanik M (2013) Natural killer cell-mediated contact sensitivity develops rapidly and depends on interferon-alpha, interferon-gamma and interleukin-12. Immunology 140(1):98–110PubMedCentralCrossRefPubMedGoogle Scholar
  34. 34.
    Heesch K, Raczkowski F, Schumacher V, Hunemorder S, Panzer U, Mittrucker HW (2014) The function of the chemokine receptor CXCR6 in the T cell response of mice against Listeria monocytogenes. PLoS One 9(5):e97701PubMedCentralCrossRefPubMedGoogle Scholar
  35. 35.
    Tse SW, Radtke AJ, Espinosa DA, Cockburn IA, Zavala F (2014) The chemokine receptor CXCR6 is required for the maintenance of liver memory CD8(+) T cells specific for infectious pathogens. J Infect Dis 210(9):1508–1516PubMedCentralCrossRefPubMedGoogle Scholar
  36. 36.
    Liaskou E, Jeffery LE, Trivedi PJ, Reynolds GM, Suresh S, Bruns T, Adams DH, Sansom DM, Hirschfield GM (2014) Loss of CD28 expression by liver-infiltrating T cells contributes to pathogenesis of primary sclerosing cholangitis. Gastroenterology. 147(1):221e7–232e7Google Scholar
  37. 37.
    Karlmark KR, Weiskirchen R, Zimmermann HW, Gassler N, Ginhoux F, Weber C, Merad M, Luedde T, Trautwein C, Tacke F (2009) Hepatic recruitment of the inflammatory Gr1 + monocyte subset upon liver injury promotes hepatic fibrosis. Hepatology 50(1):261–274CrossRefPubMedGoogle Scholar
  38. 38.
    Pellicoro A, Ramachandran P, Iredale JP, Fallowfield JA (2014) Liver fibrosis and repair: immune regulation of wound healing in a solid organ. Nat Rev Immunol 14(3):181–194CrossRefPubMedGoogle Scholar
  39. 39.
    Xu H, Xu W, Chu Y, Gong Y, Jiang Z, Xiong S (2005) Involvement of up-regulated CXC chemokine ligand 16/scavenger receptor that binds phosphatidylserine and oxidized lipoprotein in endotoxin-induced lethal liver injury via regulation of T-cell recruitment and adhesion. Infect Immun 73(7):4007–4016PubMedCentralCrossRefPubMedGoogle Scholar
  40. 40.
    Xu HB, Gong YP, Cheng J, Chu YW, Xiong SD (2005) CXCL16 participates in pathogenesis of immunological liver injury by regulating T lymphocyte infiltration in liver tissue. World J Gastroenterol 11(32):4979–4985PubMedCentralCrossRefPubMedGoogle Scholar
  41. 41.
    Shimaoka T, Seino K, Kume N, Minami M, Nishime C, Suematsu M, Kita T, Taniguchi M, Matsushima K, Yonehara S (2007) Critical role for CXC chemokine ligand 16 (SR-PSOX) in Th1 response mediated by NKT cells. J Immunol 179(12):8172–8179CrossRefPubMedGoogle Scholar
  42. 42.
    Nakano M, Saeki C, Takahashi H, Homma S, Tajiri H, Zeniya M (2012) Activated natural killer T cells producing interferon-gamma elicit promoting activity to murine dendritic cell-based autoimmune hepatic inflammation. Clin Exp Immunol 170(3):274–282PubMedCentralCrossRefPubMedGoogle Scholar
  43. 43.
    Galle J, Hansen-Hagge T, Wanner C, Seibold S (2006) Impact of oxidized low density lipoprotein on vascular cells. Atherosclerosis 185(2):219–226CrossRefPubMedGoogle Scholar
  44. 44.
    Gutwein P, Abdel-Bakky MS, Schramme A, Doberstein K, Kampfer-Kolb N, Amann K, Hauser IA, Obermuller N, Bartel C, Abdel-Aziz AA et al (2009) CXCL16 is expressed in podocytes and acts as a scavenger receptor for oxidized low-density lipoprotein. Am J Pathol 174(6):2061–2072PubMedCentralCrossRefPubMedGoogle Scholar
  45. 45.
    Aslanian AM, Charo IF (2006) Targeted disruption of the scavenger receptor and chemokine CXCL16 accelerates atherosclerosis. Circulation 114(6):583–590CrossRefPubMedGoogle Scholar
  46. 46.
    Izquierdo MC, Martin-Cleary C, Fernandez-Fernandez B, Elewa U, Sanchez-Nino MD, Carrero JJ, Ortiz A (2014) CXCL16 in kidney and cardiovascular injury. Cytokine Growth Factor Rev 25(3):317–325CrossRefPubMedGoogle Scholar
  47. 47.
    Saleh I, Ali Z, Hammad M, Wilson F, Hamada F, Abd-Ellah M, Walker, Khan I, Ashfaq I (2015) Stem cell intervention ameliorates epigallocatechin-3-gallate/lipopolysaccharide-induced hepatotoxicity in mice. Hum Exp Toxicol. doi: 10.1177/0960327115572707 Google Scholar
  48. 48.
    Schrage A, Wechsung K, Neumann K, Schumann M, Schulzke JD, Engelhardt B, Zeitz M, Hamann A, Klugewitz K (2008) Enhanced T cell transmigration across the murine liver sinusoidal endothelium is mediated by transcytosis and surface presentation of chemokines. Hepatology 48(4):1262–1272CrossRefPubMedGoogle Scholar
  49. 49.
    Omenetti A, Syn WK, Jung Y, Francis H, Porrello A, Witek RP, Choi SS, Yang L, Mayo MJ, Gershwin ME et al (2009) Repair-related activation of hedgehog signaling promotes cholangiocyte chemokine production. Hepatology 50(2):518–527PubMedCentralCrossRefPubMedGoogle Scholar
  50. 50.
    Rollag H, Asberg A, Ueland T, Hartmann A, Jardine AG, Humar A, Pescovitz MD, Bignamini AA, Aukrust P (2012) Treatment of cytomegalovirus disease in solid organ transplant recipients: markers of inflammation as predictors of outcome. Transplantation 94(10):1060–1065CrossRefPubMedGoogle Scholar
  51. 51.
    Xu Y, Ganem D (2007) Induction of chemokine production by latent Kaposi’s sarcoma-associated herpesvirus infection of endothelial cells. J Gen Virol 88(Pt 1):46–50CrossRefPubMedGoogle Scholar
  52. 52.
    Araki-Sasaki K, Tanaka T, Ebisuno Y, Kanda H, Umemoto E, Hayashi K, Miyasaka M (2006) Dynamic expression of chemokines and the infiltration of inflammatory cells in the HSV-infected cornea and its associated tissues. Ocul Immunol Inflamm 14(5):257–266CrossRefPubMedGoogle Scholar
  53. 53.
    Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray, F (2013) GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC Cancer Base No. 11 [Internet]. International Agency for Research on Cancer, Lyon, France. Available from: Accessed 16 Jan 2015
  54. 54.
    Matsushita K, Toiyama Y, Tanaka K, Saigusa S, Hiro J, Uchida K, Uchida K, Inoue Y, Kusunoki M (2012) Soluble CXCL16 in preoperative serum is a novel prognostic marker and predicts recurrence of liver metastases in colorectal cancer patients. Ann Surg Oncol 287(Suppl 3):S518–S527CrossRefGoogle Scholar
  55. 55.
    Santhekadur PK, Das SK, Gredler R, Chen D, Srivastava J, Robertson C, Baldwin AS Jr, Fisher PB, Sarkar D (2012) Multifunction protein staphylococcal nuclease domain containing 1 (SND1) promotes tumor angiogenesis in human hepatocellular carcinoma through novel pathway that involves nuclear factor kappaB and miR-221. J Biol Chem 287(17):13952–13958PubMedCentralCrossRefPubMedGoogle Scholar
  56. 56.
    Vansaun MN, Mendonsa AM, Lee Gorden D (2013) Hepatocellular proliferation correlates with inflammatory cell and cytokine changes in a murine model of nonalchoholic fatty liver disease. PLoS One 8(9):e73054PubMedCentralCrossRefPubMedGoogle Scholar
  57. 57.
    Wang YH, Dong YY, Wang WM, Xie XY, Wang ZM, Chen RX, Chen J, Gao DM, Cui JF, Ren ZG (2013) Vascular endothelial cells facilitated HCC invasion and metastasis through the Akt and NF-kappaB pathways induced by paracrine cytokines. J Exp Clin Cancer Res 32(1):51PubMedCentralCrossRefPubMedGoogle Scholar
  58. 58.
    Mossanen JC, Tacke F (2013) Role of lymphocytes in liver cancer. Oncoimmunology 2(11):e26468PubMedCentralCrossRefPubMedGoogle Scholar
  59. 59.
    Kee JY, Ito A, Hojo S, Hashimoto I, Igarashi Y, Tsukada K, Irimura T, Shibahara N, Nakayama T, Yoshie O et al (2013) Chemokine CXCL16 suppresses liver metastasis of colorectal cancer via augmentation of tumor-infiltrating natural killer T cells in a murine model. Oncol Rep 29(3):975–982PubMedGoogle Scholar
  60. 60.
    Kee JY, Ito A, Hojo S, Hashimoto I, Igarashi Y, Tsuneyama K, Tsukada K, Irimura T, Shibahara N, Takasaki I et al (2014) CXCL16 suppresses liver metastasis of colorectal cancer by promoting TNF-alpha-induced apoptosis by tumor-associated macrophages. BMC Cancer 14:949PubMedCentralCrossRefPubMedGoogle Scholar
  61. 61.
    Cullen R, Germanov E, Shimaoka T, Johnston B (2009) Enhanced tumor metastasis in response to blockade of the chemokine receptor CXCR6 is overcome by NKT cell activation. J Immunol 183(9):5807–5815CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of Medicine III, Medical Faculty of the RWTHRWTH University-Hospital AachenAachenGermany

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