Skip to main content

Innate Immunity and Disorders of the Liver

  • Chapter
  • First Online:
Liver Immunology

Abstract

The liver as an organ, which is continuously exposed to intestinal microbiota-derived innate immune stimuli contained within portal venous blood. This chapter will review our knowledge on innate immune responses in the liver and will discuss the impact of hepatic innate immunity on liver disorders.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Blander JM, Sander LE. Beyond pattern recognition: five immune checkpoints for scaling the microbial threat. Nat Rev Immunol. 2012;12:215–25.

    PubMed  CAS  Google Scholar 

  2. Klein I, Cornejo JC, Polakos NK, et al. Kupffer cell heterogeneity: functional properties of bone marrow derived and sessile hepatic macrophages. Blood. 2007;110:4077–85.

    PubMed  CAS  Google Scholar 

  3. Thomson AW, Knolle PA. Antigen-presenting cell function in the tolerogenic liver environment. Nat Rev Immunol. 2010;10: 753–66.

    PubMed  CAS  Google Scholar 

  4. van Oosten M, van Amersfoort ES, van Berkel TJ, Kuiper J. Scavenger receptor-like receptors for the binding of lipopolysaccharide and lipoteichoic acid to liver endothelial and Kupffer cells. J Endotoxin Res. 2001;7:381–4.

    PubMed  Google Scholar 

  5. Petrasek J, Bala S, Csak T, et al. IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice. J Clin Invest. 2012;122:3476–89.

    PubMed  CAS  Google Scholar 

  6. Knolle PA, Uhrig A, Protzer U, et al. Interleukin-10 expression is autoregulated at the transcriptional level in human and murine Kupffer cells. Hepatology. 1998;27:93–9.

    PubMed  CAS  Google Scholar 

  7. You Q, Cheng L, Kedl RM, Ju C. Mechanism of T cell tolerance induction by murine hepatic Kupffer cells. Hepatology. 2008;48: 978–90.

    PubMed  CAS  Google Scholar 

  8. Sitia G, Iannacone M, Aiolfi R, et al. Kupffer cells hasten resolution of liver immunopathology in mouse models of viral hepatitis. PLoS Pathog. 2011;7:e1002061.

    PubMed  CAS  Google Scholar 

  9. Breous E, Somanathan S, Vandenberghe LH, Wilson JM. Hepatic regulatory T cells and Kupffer cells are crucial mediators of systemic T cell tolerance to antigens targeting murine liver. Hepatology. 2009;50:612–21.

    PubMed  CAS  Google Scholar 

  10. Wiegard C, Frenzel C, Herkel J, Kallen KJ, Schmitt E, Lohse AW. Murine liver antigen presenting cells control suppressor activity of CD4+CD25+ regulatory T cells. Hepatology. 2005;42:193–9.

    PubMed  CAS  Google Scholar 

  11. Kern M, Popov A, Scholz K, et al. Virally infected mouse liver endothelial cells trigger CD8+ T-cell immunity. Gastroenterology. 2010;138:336–46.

    PubMed  CAS  Google Scholar 

  12. Vinas O, Bataller R, Sancho-Bru P, et al. Human hepatic stellate cells show features of antigen-presenting cells and stimulate lymphocyte proliferation. Hepatology. 2003;38:919–29.

    PubMed  CAS  Google Scholar 

  13. Steptoe RJ, Fu F, Li W, et al. Augmentation of dendritic cells in murine organ donors by Flt3 ligand alters the balance between transplant tolerance and immunity. J Immunol. 1997;159: 5483–91.

    PubMed  CAS  Google Scholar 

  14. Abe M, Tokita D, Raimondi G, Thomson AW. Endotoxin modulates the capacity of CpG-activated liver myeloid DC to direct Th1-type responses. Eur J Immunol. 2006;36:2483–93.

    PubMed  CAS  Google Scholar 

  15. Rutella S, Danese S, Leone G. Tolerogenic dendritic cells: cytokine modulation comes of age. Blood. 2006;108:1435–40.

    PubMed  CAS  Google Scholar 

  16. Kudo S, Matsuno K, Ezaki T, Ogawa M. A novel migration pathway for rat dendritic cells from the blood: hepatic sinusoids-lymph translocation. J Exp Med. 1997;185:777–84.

    PubMed  CAS  Google Scholar 

  17. Uwatoku R, Suematsu M, Ezaki T, et al. Kupffer cell-mediated recruitment of rat dendritic cells to the liver: roles of N-acetylgalactosamine-specific sugar receptors. Gastroenterology. 2001;121:1460–72.

    PubMed  CAS  Google Scholar 

  18. Bosma BM, Metselaar HJ, Mancham S, et al. Characterization of human liver dendritic cells in liver grafts and perfusates. Liver Transpl. 2006;12:384–93.

    PubMed  Google Scholar 

  19. Shortman K, Naik SH. Steady-state and inflammatory dendritic-cell development. Nat Rev Immunol. 2007;7:19–30.

    PubMed  CAS  Google Scholar 

  20. Takeuchi O, Akira S. MDA5/RIG-I and virus recognition. Curr Opin Immunol. 2008;20:17–22.

    PubMed  CAS  Google Scholar 

  21. Bedoui S, Whitney PG, Waithman J, et al. Cross-presentation of viral and self antigens by skin-derived CD103+ dendritic cells. Nat Immunol. 2009;10:488–95.

    PubMed  CAS  Google Scholar 

  22. Gao B, Radaeva S, Park O. Liver natural killer and natural killer T cells: immunobiology and emerging roles in liver diseases. J Leukoc Biol. 2009;86:513–28.

    PubMed  CAS  Google Scholar 

  23. Wisse E, van’t Noordende JM, van der Meulen J, Daems WT. The pit cell: description of a new type of cell occurring in rat liver sinusoids and peripheral blood. Cell Tissue Res. 1976;173:423–35.

    PubMed  CAS  Google Scholar 

  24. Hokeness KL, Kuziel WA, Biron CA, Salazar-Mather TP. Monocyte chemoattractant protein-1 and CCR2 interactions are required for IFN-alpha/beta-induced inflammatory responses and antiviral defense in liver. J Immunol. 2005;174:1549–56.

    PubMed  CAS  Google Scholar 

  25. Bryceson YT, Long EO. Line of attack: NK cell specificity and integration of signals. Curr Opin Immunol. 2008;20:344–52.

    PubMed  CAS  Google Scholar 

  26. Maini MK, Peppa D. NK cells: a double-edged sword in chronic hepatitis B virus infection. Front Immunol. 2013;4:57.

    PubMed  Google Scholar 

  27. Nebbia G, Peppa D, Schurich A, et al. Upregulation of the Tim-3/galectin-9 pathway of T cell exhaustion in chronic hepatitis B virus infection. PLoS One. 2012;7:e47648.

    PubMed  CAS  Google Scholar 

  28. Ju Y, Hou N, Meng J, et al. T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) mediates natural killer cell suppression in chronic hepatitis B. J Hepatol. 2010;52:322–9.

    PubMed  CAS  Google Scholar 

  29. Lanier LL. Up on the tightrope: natural killer cell activation and inhibition. Nat Immunol. 2008;9:495–502.

    PubMed  CAS  Google Scholar 

  30. Jiang L, Yuan CM, Hubacheck J, et al. Variable CD52 expression in mature T cell and NK cell malignancies: implications for alemtuzumab therapy. Br J Haematol. 2009;145:173–9.

    PubMed  CAS  Google Scholar 

  31. Tang XZ, Jo J, Tan AT, et al. IL-7 licenses activation of human liver intrasinusoidal mucosal-associated invariant T cells. J Immunol. 2013;190(7):3142–52.

    PubMed  CAS  Google Scholar 

  32. Tiegs G, Hentschel J, Wendel A. A T cell-dependent experimental liver injury in mice inducible by concanavalin A. J Clin Invest. 1992;90:196–203.

    PubMed  CAS  Google Scholar 

  33. Takeda K, Hayakawa Y, Van Kaer L, Matsuda H, Yagita H, Okumura K. Critical contribution of liver natural killer T cells to a murine model of hepatitis. Proc Natl Acad Sci U S A. 2000;97:5498–503.

    PubMed  CAS  Google Scholar 

  34. Minagawa M, Deng Q, Liu ZX, Tsukamoto H, Dennert G. Activated natural killer T cells induce liver injury by Fas and tumor necrosis factor-alpha during alcohol consumption. Gastroenterology. 2004;126:1387–99.

    PubMed  CAS  Google Scholar 

  35. Tajiri K, Shimizu Y, Tsuneyama K, Sugiyama T. Role of liver-infiltrating CD3+CD56+ natural killer T cells in the pathogenesis of nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol. 2009;21:673–80.

    PubMed  CAS  Google Scholar 

  36. Jiang W, Sun R, Wei H, Tian Z. Toll-like receptor 3 ligand attenuates LPS-induced liver injury by down-regulation of toll-like receptor 4 expression on macrophages. Proc Natl Acad Sci U S A. 2005;102:17077–82.

    PubMed  CAS  Google Scholar 

  37. Abe T, Kawamura H, Kawabe S, Watanabe H, Gejyo F, Abo T. Liver injury due to sequential activation of natural killer cells and natural killer T cells by carrageenan. J Hepatol. 2002;36:614–23.

    PubMed  CAS  Google Scholar 

  38. Zeissig S, Murata K, Sweet L, et al. Hepatitis B virus-induced lipid alterations contribute to natural killer T cell-dependent protective immunity. Nat Med. 2012;18:1060–8.

    PubMed  CAS  Google Scholar 

  39. Kakimi K, Guidotti LG, Koezuka Y, Chisari FV. Natural killer T cell activation inhibits hepatitis B virus replication in vivo. J Exp Med. 2000;192:921–30.

    PubMed  CAS  Google Scholar 

  40. Lucas M, Gadola S, Meier U, et al. Frequency and phenotype of circulating Valpha24/Vbeta11 double-positive natural killer T cells during hepatitis C virus infection. J Virol. 2003;77:2251–7.

    PubMed  CAS  Google Scholar 

  41. Yamagiwa S, Matsuda Y, Ichida T, et al. Sustained response to interferon-alpha plus ribavirin therapy for chronic hepatitis C is closely associated with increased dynamism of intrahepatic natural killer and natural killer T cells. Hepatol Res. 2008;38:664–72.

    PubMed  CAS  Google Scholar 

  42. Semmling V, Lukacs-Kornek V, Thaiss CA, et al. Alternative cross-priming through CCL17-CCR4-mediated attraction of CTLs toward NKT cell-licensed DCs. Nat Immunol. 2010;11:313–20.

    PubMed  CAS  Google Scholar 

  43. Vanderkerken K, Bouwens L, Wisse E. Characterization of a phenotypically and functionally distinct subset of large granular lymphocytes (pit cells) in rat liver sinusoids. Hepatology. 1990;12:70–5.

    PubMed  CAS  Google Scholar 

  44. Tacke F. Functional role of intrahepatic monocyte subsets for the progression of liver inflammation and liver fibrosis in vivo. Fibrogenesis Tissue Repair. 2012;5 Suppl 1:S27.

    PubMed  Google Scholar 

  45. Geissmann F, Jung S, Littman DR. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity. 2003;19:71–82.

    PubMed  CAS  Google Scholar 

  46. McDonald B, Kubes P. Neutrophils and intravascular immunity in the liver during infection and sterile inflammation. Toxicol Pathol. 2012;40:157–65.

    PubMed  CAS  Google Scholar 

  47. Jenne CN, Wong CH, Zemp FJ, et al. Neutrophils recruited to sites of infection protect from virus challenge by releasing neutrophil extracellular traps. Cell Host Microbe. 2013;13:169–80.

    PubMed  CAS  Google Scholar 

  48. Sitia G, Isogawa M, Iannacone M, Campbell IL, Chisari FV, Guidotti LG. MMPs are required for recruitment of antigen-nonspecific mononuclear cells into the liver by CTLs. J Clin Invest. 2004;113:1158–67.

    PubMed  CAS  Google Scholar 

  49. Jaeschke H. Reactive oxygen and mechanisms of inflammatory liver injury: Present concepts. J Gastroenterol Hepatol. 2011;26 Suppl 1:173–9.

    PubMed  CAS  Google Scholar 

  50. Iannacone M, Sitia G, Isogawa M, et al. Platelets mediate cytotoxic T lymphocyte-induced liver damage. Nat Med. 2005;11:1167–9.

    PubMed  CAS  Google Scholar 

  51. Lang PA, Contaldo C, Georgiev P, et al. Aggravation of viral hepatitis by platelet-derived serotonin. Nat Med. 2008;14:756–61.

    PubMed  CAS  Google Scholar 

  52. Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol. 2013;13:34–45.

    PubMed  CAS  Google Scholar 

  53. Gao B, Jeong WI, Tian Z. Liver: an organ with predominant innate immunity. Hepatology. 2008;47:729–36.

    PubMed  CAS  Google Scholar 

  54. Wang B, Trippler M, Pei R, et al. Toll-like receptor activated human and murine hepatic stellate cells are potent regulators of hepatitis C virus replication. J Hepatol. 2009;51:1037–45.

    PubMed  CAS  Google Scholar 

  55. Wu J, Meng Z, Jiang M, et al. Hepatitis B virus suppresses toll-like receptor-mediated innate immune responses in murine parenchymal and nonparenchymal liver cells. Hepatology. 2009;49: 1132–40.

    PubMed  CAS  Google Scholar 

  56. Saito T, Owen DM, Jiang F, Marcotrigiano J, Gale Jr M. Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA. Nature. 2008;454:523–7.

    PubMed  CAS  Google Scholar 

  57. Ebert G, Poeck H, Lucifora J, et al. 5′ Triphosphorylated small interfering RNAs control replication of hepatitis B virus and induce an interferon response in human liver cells and mice. Gastroenterology. 2011;141:696–706, e1–3.

    Google Scholar 

  58. Biswas SK, Lopez-Collazo E. Endotoxin tolerance: new mechanisms, molecules and clinical significance. Trends Immunol. 2009;30:475–87.

    PubMed  CAS  Google Scholar 

  59. De Creus A, Abe M, Lau AH, Hackstein H, Raimondi G, Thomson AW. Low TLR4 expression by liver dendritic cells correlates with reduced capacity to activate allogeneic T cells in response to endotoxin. J Immunol. 2005;174:2037–45.

    PubMed  Google Scholar 

  60. Limmer A, Ohl J, Kurts C, et al. Efficient presentation of exogenous antigen by liver endothelial cells to CD8+ T cells results in antigen-specific T-cell tolerance. Nat Med. 2000;6:1348–54.

    PubMed  CAS  Google Scholar 

  61. van Egmond M, van Garderen E, van Spriel AB, et al. FcalphaRI-positive liver Kupffer cells: reappraisal of the function of immunoglobulin A in immunity. Nat Med. 2000;6:680–5.

    PubMed  Google Scholar 

  62. Klein C, Wustefeld T, Assmus U, et al. The IL-6-gp130-STAT3 pathway in hepatocytes triggers liver protection in T cell-mediated liver injury. J Clin Invest. 2005;115:860–9.

    PubMed  CAS  Google Scholar 

  63. Gehring S, Dickson EM, San Martin ME, et al. Kupffer cells abrogate cholestatic liver injury in mice. Gastroenterology. 2006;130: 810–22.

    PubMed  CAS  Google Scholar 

  64. Knolle PA, Gerken G. Local control of the immune response in the liver. Immunol Rev. 2000;174:21–34.

    PubMed  CAS  Google Scholar 

  65. Baumann H, Gauldie J. The acute phase response. Immunol Today. 1994;15:74–80.

    PubMed  CAS  Google Scholar 

  66. Galun E, Rose-John S. The regenerative activity of interleukin-6. Methods Mol Biol. 2013;982:59–77.

    PubMed  Google Scholar 

  67. Lee WY, Moriarty TJ, Wong CH, et al. An intravascular immune response to Borrelia burgdorferi involves Kupffer cells and iNKT cells. Nat Immunol. 2010;11:295–302.

    PubMed  CAS  Google Scholar 

  68. Protzer U, Maini MK, Knolle PA. Living in the liver: hepatic infections. Nat Rev Immunol. 2012;12:201–13.

    PubMed  CAS  Google Scholar 

  69. Taniguchi M, Seino K, Nakayama T. The NKT cell system: bridging innate and acquired immunity. Nat Immunol. 2003;4:1164–5.

    PubMed  CAS  Google Scholar 

  70. Popov A, Abdullah Z, Wickenhauser C, et al. Indoleamine 2,3-dioxygenase-expressing dendritic cells form suppurative granulomas following Listeria monocytogenes infection. J Clin Invest. 2006;116:3160–70.

    PubMed  CAS  Google Scholar 

  71. Egen JG, Rothfuchs AG, Feng CG, Winter N, Sher A, Germain RN. Macrophage and T cell dynamics during the development and disintegration of mycobacterial granulomas. Immunity. 2008;28: 271–84.

    PubMed  CAS  Google Scholar 

  72. Volkman HE, Pozos TC, Zheng J, Davis JM, Rawls JF, Ramakrishnan L. Tuberculous granuloma induction via interaction of a bacterial secreted protein with host epithelium. Science. 2010;327:466–9.

    PubMed  CAS  Google Scholar 

  73. Davis JM, Ramakrishnan L. The role of the granuloma in expansion and dissemination of early tuberculous infection. Cell. 2009;136:37–49.

    PubMed  CAS  Google Scholar 

  74. Kumar KA, Sano G, Boscardin S, et al. The circumsporozoite protein is an immunodominant protective antigen in irradiated sporozoites. Nature. 2006;444:937–40.

    PubMed  CAS  Google Scholar 

  75. Usynin I, Klotz C, Frevert U. Malaria circumsporozoite protein inhibits the respiratory burst in Kupffer cells. Cell Microbiol. 2007;9:2610–28.

    PubMed  CAS  Google Scholar 

  76. Pradel G, Frevert U. Malaria sporozoites actively enter and pass through rat Kupffer cells prior to hepatocyte invasion. Hepatology. 2001;33:1154–65.

    PubMed  CAS  Google Scholar 

  77. Gowda DC. TLR-mediated cell signaling by malaria GPIs. Trends Parasitol. 2007;23:596–604.

    PubMed  CAS  Google Scholar 

  78. Lanford RE, Feng Z, Chavez D, et al. Acute hepatitis A virus infection is associated with a limited type I interferon response and persistence of intrahepatic viral RNA. Proc Natl Acad Sci U S A. 2011;108:11223–8.

    PubMed  CAS  Google Scholar 

  79. Dolganiuc A, Oak S, Kodys K, et al. Hepatitis C core and nonstructural 3 proteins trigger toll-like receptor 2-mediated pathways and inflammatory activation. Gastroenterology. 2004;127: 1513–24.

    PubMed  CAS  Google Scholar 

  80. Cooper A, Tal G, Lider O, Shaul Y. Cytokine induction by the hepatitis B virus capsid in macrophages is facilitated by membrane heparan sulfate and involves TLR2. J Immunol. 2005;175:3165–76.

    PubMed  CAS  Google Scholar 

  81. Hosel M, Quasdorff M, Wiegmann K, et al. Not interferon, but interleukin-6 controls early gene expression in hepatitis B virus infection. Hepatology. 2009;50:1773–82.

    PubMed  Google Scholar 

  82. Dunn C, Peppa D, Khanna P, et al. Temporal analysis of early immune responses in patients with acute hepatitis B virus infection. Gastroenterology. 2009;137:1289–300.

    PubMed  CAS  Google Scholar 

  83. Wieland S, Thimme R, Purcell RH, Chisari FV. Genomic analysis of the host response to hepatitis B virus infection. Proc Natl Acad Sci U S A. 2004;101:6669–74.

    PubMed  CAS  Google Scholar 

  84. Veerapu NS, Raghuraman S, Liang TJ, Heller T, Rehermann B. Sporadic reappearance of minute amounts of hepatitis C virus RNA after successful therapy stimulates cellular immune responses. Gastroenterology. 2011;140:676–85e1.

    PubMed  CAS  Google Scholar 

  85. Rehermann B, Ferrari C, Pasquinelli C, Chisari FV. The hepatitis B virus persists for decades after patients’ recovery from acute viral hepatitis despite active maintenance of a cytotoxic T-lymphocyte response. Nat Med. 1996;2:1104–8.

    PubMed  CAS  Google Scholar 

  86. Rehermann B, Nascimbeni M. Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol. 2005;5:215–29.

    PubMed  CAS  Google Scholar 

  87. Guidotti LG, Ando K, Hobbs MV, et al. Cytotoxic T lymphocytes inhibit hepatitis B virus gene expression by a noncytolytic mechanism in transgenic mice. Proc Natl Acad Sci U S A. 1994;91:3764–8.

    PubMed  CAS  Google Scholar 

  88. Guidotti LG, Borrow P, Brown A, McClary H, Koch R, Chisari FV. Noncytopathic clearance of lymphocytic choriomeningitis virus from the hepatocyte. J Exp Med. 1999;189:1555–64.

    PubMed  CAS  Google Scholar 

  89. Bauhofer O, Ruggieri A, Schmid B, Schirmacher P, Bartenschlager R. Persistence of HCV in quiescent hepatic cells under conditions of an interferon-induced antiviral response. Gastroenterology. 2012;143:429–38e8.

    PubMed  CAS  Google Scholar 

  90. Guidotti LG, Chisari FV. Noncytolytic control of viral infections by the innate and adaptive immune response. Annu Rev Immunol. 2001;19:65–91.

    PubMed  CAS  Google Scholar 

  91. Murray JM, Wieland SF, Purcell RH, Chisari FV. Dynamics of hepatitis B virus clearance in chimpanzees. Proc Natl Acad Sci U S A. 2005;102:17780–5.

    PubMed  CAS  Google Scholar 

  92. Kurts C, Robinson BW, Knolle PA. Cross-priming in health and disease. Nat Rev Immunol. 2010;10:403–14.

    PubMed  CAS  Google Scholar 

  93. Gale Jr M, Foy EM. Evasion of intracellular host defence by hepatitis C virus. Nature. 2005;436:939–45.

    PubMed  CAS  Google Scholar 

  94. Qu L, Lemon SM. Hepatitis A and hepatitis C viruses: divergent infection outcomes marked by similarities in induction and evasion of interferon responses. Semin Liver Dis. 2010;30:319–32.

    PubMed  CAS  Google Scholar 

  95. Alexopoulou L, Holt AC, Medzhitov R, Flavell RA. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature. 2001;413:732–8.

    PubMed  CAS  Google Scholar 

  96. Li XD, Sun L, Seth RB, Pineda G, Chen ZJ. Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity. Proc Natl Acad Sci U S A. 2005;102:17717–22.

    PubMed  CAS  Google Scholar 

  97. Meylan E, Curran J, Hofmann K, et al. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature. 2005;437:1167–72.

    PubMed  CAS  Google Scholar 

  98. Foy E, Li K, Wang C, et al. Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science. 2003;300:1145–8.

    PubMed  CAS  Google Scholar 

  99. Yang Y, Liang Y, Qu L, et al. Disruption of innate immunity due to mitochondrial targeting of a picornaviral protease precursor. Proc Natl Acad Sci U S A. 2007;104:7253–8.

    PubMed  CAS  Google Scholar 

  100. Qu L, Feng Z, Yamane D, et al. Disruption of TLR3 signaling due to cleavage of TRIF by the hepatitis A virus protease-polymerase processing intermediate, 3CD. PLoS Pathog. 2011;7:e1002169.

    PubMed  CAS  Google Scholar 

  101. Desai MM, Gong B, Chan T, et al. Differential, type I interferon-mediated autophagic trafficking of hepatitis C virus proteins in mouse liver. Gastroenterology. 2011;141:674–85, 685e1–6.

    Google Scholar 

  102. Amadei B, Urbani S, Cazaly A, et al. Activation of natural killer cells during acute infection with hepatitis C virus. Gastroenterology. 2010;138:1536–45.

    PubMed  CAS  Google Scholar 

  103. Chen L, Borozan I, Feld J, et al. Hepatic gene expression discriminates responders and nonresponders in treatment of chronic hepatitis C viral infection. Gastroenterology. 2005;128:1437–44.

    PubMed  CAS  Google Scholar 

  104. Heim MH. Innate immunity and HCV. J Hepatol. 2013;58:564–74.

    PubMed  CAS  Google Scholar 

  105. Wohlleber D, Kashkar H, Gartner K, et al. TNF-induced target cell killing by CTL activated through cross-presentation. Cell Rep. 2012;2:478–87.

    PubMed  CAS  Google Scholar 

  106. Canbay A, Feldstein AE, Higuchi H, et al. Kupffer cell engulfment of apoptotic bodies stimulates death ligand and cytokine expression. Hepatology. 2003;38:1188–98.

    PubMed  CAS  Google Scholar 

  107. McDonald B, Pittman K, Menezes GB, et al. Intravascular danger signals guide neutrophils to sites of sterile inflammation. Science. 2010;330:362–6.

    PubMed  CAS  Google Scholar 

  108. Wu J, Lu M, Meng Z, et al. Toll-like receptor-mediated control of HBV replication by nonparenchymal liver cells in mice. Hepatology. 2007;46:1769–78.

    PubMed  CAS  Google Scholar 

  109. Lang PA, Recher M, Honke N, et al. Tissue macrophages suppress viral replication and prevent severe immunopathology in an interferon-I-dependent manner in mice. Hepatology. 2010;52:25–32.

    PubMed  CAS  Google Scholar 

  110. Schulz O, Diebold SS, Chen M, et al. Toll-like receptor 3 promotes cross-priming to virus-infected cells. Nature. 2005;433:887–92.

    PubMed  CAS  Google Scholar 

  111. Sancho D, Joffre OP, Keller AM, et al. Identification of a dendritic cell receptor that couples sensing of necrosis to immunity. Nature. 2009;458:899–903.

    PubMed  CAS  Google Scholar 

  112. Shi C, Velazquez P, Hohl TM, Leiner I, Dustin ML, Pamer EG. Monocyte trafficking to hepatic sites of bacterial infection is chemokine independent and directed by focal intercellular adhesion molecule-1 expression. J Immunol. 2010;184:6266–74.

    PubMed  CAS  Google Scholar 

  113. Simonin Y, Vegna S, Akkari L, et al. Lymphotoxin signaling is initiated by the viral polymerase in HCV-linked tumorigenesis. PLoS Pathog. 2013;9:e1003234.

    PubMed  CAS  Google Scholar 

  114. Seki E, De Minicis S, Osterreicher CH, et al. TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat Med. 2007;13:1324–32.

    PubMed  CAS  Google Scholar 

  115. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2001;357:539–45.

    PubMed  CAS  Google Scholar 

  116. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    PubMed  CAS  Google Scholar 

  117. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70.

    PubMed  CAS  Google Scholar 

  118. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454:436–44.

    PubMed  CAS  Google Scholar 

  119. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet. 2003;362:1907–17.

    PubMed  Google Scholar 

  120. Mostafa MH, Sheweita SA, O’Connor PJ. Relationship between schistosomiasis and bladder cancer. Clin Microbiol Rev. 1999;12:97–111.

    PubMed  CAS  Google Scholar 

  121. Nishiyama R, Kanai T, Abe J, et al. Hepatocellular carcinoma associated with autoimmune hepatitis. J Hepatobiliary Pancreat Surg. 2004;11:215–9.

    PubMed  Google Scholar 

  122. Fan JG, Farrell GC. Epidemiology of non-alcoholic fatty liver disease in China. J Hepatol. 2009;50:204–10.

    PubMed  Google Scholar 

  123. Maggs JR, Chapman RW. An update on primary sclerosing cholangitis. Curr Opin Gastroenterol. 2008;24:377–83.

    PubMed  Google Scholar 

  124. Park EJ, Lee JH, Yu GY, et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell. 2010;140:197–208.

    PubMed  CAS  Google Scholar 

  125. Haybaeck J, Zeller N, Wolf MJ, et al. A lymphotoxin-driven pathway to hepatocellular carcinoma. Cancer Cell. 2009;16:295–308.

    PubMed  CAS  Google Scholar 

  126. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140:883–99.

    PubMed  CAS  Google Scholar 

  127. Lukashev M, LePage D, Wilson C, et al. Targeting the lymphotoxin-beta receptor with agonist antibodies as a potential cancer therapy. Cancer Res. 2006;66:9617–24.

    PubMed  CAS  Google Scholar 

  128. Wolf MJ, Seleznik GM, Zeller N, Heikenwalder M. The unexpected role of lymphotoxin beta receptor signaling in carcinogenesis: from lymphoid tissue formation to liver and prostate cancer development. Oncogene. 2010;29:5006–18.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Mathias Heikenwalder .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this chapter

Cite this chapter

Heikenwalder, M., Knolle, P., Protzer, U. (2014). Innate Immunity and Disorders of the Liver. In: Gershwin, M., Vierling, J., Manns, M. (eds) Liver Immunology. Springer, Cham. https://doi.org/10.1007/978-3-319-02096-9_6

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-02096-9_6

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-02095-2

  • Online ISBN: 978-3-319-02096-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics