The liver is a key, frontline immune tissue. Ideally positioned to detect pathogens entering the body via the gut, the liver appears designed to detect, capture, and clear bacteria, viruses, and macromolecules. Containing the largest collection of phagocytic cells in the body, this organ is an important barrier between us and the outside world. Importantly, as portal blood also transports a large number of foreign but harmless molecules (e.g., food antigens), the liver's default immune status is anti-inflammatory or immunotolerant; however, under appropriate conditions, the liver is able to mount a rapid and robust immune response. This balance between immunity and tolerance is essential to liver function. Excessive inflammation in the absence of infection leads to sterile liver injury, tissue damage, and remodeling; insufficient immunity allows for chronic infection and cancer. Dynamic interactions between the numerous populations of immune cells in the liver are key to maintaining this balance and overall tissue health.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Berg RD. 1.  1995. Bacterial translocation from the gastrointestinal tract. Trends Microbiol 3:149–54 [Google Scholar]
  2. Lumsden AB, Henderson JM, Kutner MH. 2.  1988. Endotoxin levels measured by a chromogenic assay in portal, hepatic and peripheral venous blood in patients with cirrhosis. Hepatology 8:232–36 [Google Scholar]
  3. Son G, Kremer M, Hines IN. 3.  2010. Contribution of gut bacteria to liver pathobiology. Gastroenterol. Res. Pract. 2010:453563 https://doi.org/10.1155/2010/453563 [Crossref] [Google Scholar]
  4. Paulos CM, Wrzesinski C, Kaiser A, Hinrichs CS, Chieppa M. 4.  et al. 2007. Microbial translocation augments the function of adoptively transferred self/tumor-specific CD8+ T cells via TLR4 signaling. J. Clin. Investig. 117:2197–204 [Google Scholar]
  5. Balmer ML, Slack E, de Gottardi A, Lawson MA, Hapfelmeier S. 5.  et al. 2014. The liver may act as a firewall mediating mutualism between the host and its gut commensal microbiota. Sci. Transl. Med. 6:237ra66 [Google Scholar]
  6. Oda M, Yokomori H, Han JY. 6.  2003. Regulatory mechanisms of hepatic microcirculation. Clin. Hemorheol. Microcirc. 29:167–82 [Google Scholar]
  7. Bilzer M, Roggel F, Gerbes AL. 7.  2006. Role of Kupffer cells in host defense and liver disease. Liver Int 26:1175–86 [Google Scholar]
  8. Helmy KY, Katschke KJ Jr., Gorgani NN, Kljavin NM. Elliott JM. 8.  et al. 2006. CRIg: a macrophage complement receptor required for phagocytosis of circulating pathogens. Cell 124:915–27 [Google Scholar]
  9. Deniset JF, Surewaard BG, Lee WY, Kubes P. 9.  2017. Splenic Ly6Ghigh mature and Ly6Gint immature neutrophils contribute to eradication of S. . pneumoniae. J. Exp. Med. 214:1333–50 [Google Scholar]
  10. He JQ, Katschke KJ Jr., Gribling P, Suto E, Lee WP. 10.  et al. 2013. CRIg mediates early Kupffer cell responses to adenovirus. J. Leukoc. Biol. 93:301–6 [Google Scholar]
  11. Lee WY, Sanz MJ, Wong CH, Hardy PO, Salman-Dilgimen A. 11.  et al. 2014. Invariant natural killer T cells act as an extravascular cytotoxic barrier for joint-invading Lyme Borrelia. . PNAS 111:13936–41 [Google Scholar]
  12. Zeng Z, Surewaard BG, Wong CH, Geoghegan JA, Jenne CN, Kubes P. 12.  2016. CRIg functions as a macrophage pattern recognition receptor to directly bind and capture blood-borne gram-positive bacteria. Cell Host Microbe 20:99–106 [Google Scholar]
  13. Johansson AG, Sundqvist T, Skogh T. 13.  2000. IgG immune complex binding to and activation of liver cells. An in vitro study with IgG immune complexes, Kupffer cells, sinusoidal endothelial cells and hepatocytes. Int. Arch. Allergy Immunol. 121:329–36 [Google Scholar]
  14. Kosugi I, Muro H, Shirasawa H, Ito I. 14.  1992. Endocytosis of soluble IgG immune complex and its transport to lysosomes in hepatic sinusoidal endothelial cells. J. Hepatol. 16:106–14 [Google Scholar]
  15. Montalvao F, Garcia Z, Celli S, Breart B, Deguine J. 15.  2013. The mechanism of anti-CD20-mediated B cell depletion revealed by intravital imaging. J. Clin. Investig. 123:5098–103 [Google Scholar]
  16. Thanabalasuriar A, Surewaard BG, Willson ME, Neupane AS, Stover CK. 16.  et al. 2017. Bispecific antibody targets multiple Pseudomonas aeruginosa evasion mechanisms in the lung vasculature. J. Clin. Investig. 127:2249–61 [Google Scholar]
  17. Gale RP, Sparkes RS, Golde DW. 17.  1978. Bone marrow origin of hepatic macrophages (Kupffer cells) in humans. Science 201:937–38 [Google Scholar]
  18. Schulz C, Gomez PE, Chorro L, Szabo-Rogers H, Cagnard N. 18.  et al. 2012. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336:86–90 [Google Scholar]
  19. Scott CL, Zheng F, De Baetselier P Martens L, Saeys Y. 19.  et al. 2016. Bone marrow–derived monocytes give rise to self-renewing and fully differentiated Kupffer cells. Nat. Commun. 7:10321 [Google Scholar]
  20. David BA, Rezende RM, Antunes MM, Santos MM, Freitas Lopes MA. 20.  et al. 2016. Combination of mass cytometry and imaging analysis reveals origin, location, and functional repopulation of liver myeloid cells in mice. Gastroenterology 151:1176–91 [Google Scholar]
  21. Beattie L, Sawtell A, Mann J, Frame TC, Teal B. 21.  et al. 2016. Bone marrow–derived and resident liver macrophages display unique transcriptomic signatures but similar biological functions. J. Hepatol. 65:758–68 [Google Scholar]
  22. Bleriot C, Dupuis T, Jouvion G, Eberl G, Disson O, Lecuit M. 22.  2015. Liver-resident macrophage necroptosis orchestrates type 1 microbicidal inflammation and type-2-mediated tissue repair during bacterial infection. Immunity 42:145–58 [Google Scholar]
  23. Jenkins SJ, Ruckerl D, Thomas GD, Hewitson JP, Duncan S. 23.  et al. 2013. IL-4 directly signals tissue-resident macrophages to proliferate beyond homeostatic levels controlled by CSF-1. J. Exp. Med. 210:2477–91 [Google Scholar]
  24. Holdsworth RJ, Irving AD, Cuschieri A. 24.  1991. Postsplenectomy sepsis and its mortality rate: actual versus perceived risks. Br. J. Surg. 78:1031–38 [Google Scholar]
  25. Gregory SH, Sagnimeni AJ, Wing EJ. 25.  1996. Bacteria in the bloodstream are trapped in the liver and killed by immigrating neutrophils. J. Immunol. 157:2514–20 [Google Scholar]
  26. Czuczman MA, Fattouh R, van Rijn JM, Canadien V, Osborne S. 26.  et al. 2014. Listeria monocytogenes exploits efferocytosis to promote cell-to-cell spread. Nature 509:230–34 [Google Scholar]
  27. Surewaard BG, Deniset JF, Zemp FJ, Amrein M, Otto M. 27.  et al. 2016. Identification and treatment of the Staphylococcus aureus reservoir in vivo. J. Exp. Med. 213:1141–51 [Google Scholar]
  28. MacParland SA, Tsoi KM, Ouyang B, Ma XZ, Manuel J. 28.  et al. 2017. Phenotype determines nanoparticle uptake by human macrophages from liver and blood. ACS Nano 11:2428–43 [Google Scholar]
  29. 29.  Deleted in proof
  30. Shi J, Gilbert GE, Kokubo Y, Ohashi T. 30.  2001. Role of the liver in regulating numbers of circulating neutrophils. Blood 98:1226–30 [Google Scholar]
  31. Fadok VA, Bratton DL, Henson PM. 31.  2001. Phagocyte receptors for apoptotic cells: recognition, uptake, and consequences. J. Clin. Investig. 108:957–62 [Google Scholar]
  32. Grozovsky R, Hoffmeister KM, Falet H. 32.  2010. Novel clearance mechanisms of platelets. Curr. Opin. Hematol. 17:585–89 [Google Scholar]
  33. You Q, Cheng L, Kedl RM, Ju C. 33.  2008. Mechanism of T cell tolerance induction by murine hepatic Kupffer cells. Hepatology 48:978–90 [Google Scholar]
  34. Knolle P, Schlaak J, Uhrig A, Kempf P, Meyer zum Buschenfelde KH, Gerken G. 34.  1995. Human Kupffer cells secrete IL-10 in response to lipopolysaccharide (LPS) challenge. J. Hepatol. 22:226–29 [Google Scholar]
  35. Huang LR, Wohlleber D, Reisinger F, Jenne CN, Cheng RL. 35.  et al. 2013. Intrahepatic myeloid-cell aggregates enable local proliferation of CD8+ T cells and successful immunotherapy against chronic viral liver infection. Nat. Immunol. 10:574–83 [Google Scholar]
  36. Lee WY, Moriarty TJ, Wong CH, Zhou H, Strieter RM. 36.  et al. 2010. An intravascular immune response to Borrelia burgdorferi involves Kupffer cells and iNKT cells. Nat. Immunol. 11:295–302 [Google Scholar]
  37. Crispe IN. 37.  2009. The liver as a lymphoid organ. Annu. Rev. Immunol. 27:147–63 [Google Scholar]
  38. Doherty DG, O'Farrelly C. 38.  2000. Innate and adaptive lymphoid cells in the human liver. Immunol. Rev. 174:5–20 [Google Scholar]
  39. Notas G, Kisseleva T, Brenner D. 39.  2009. NK and NKT cells in liver injury and fibrosis. Clin. Immunol. 130:16–26 [Google Scholar]
  40. O'Sullivan TE, Sun JC, Lanier LL. 40.  2015. Natural killer cell memory. Immunity 43:4634–45 [Google Scholar]
  41. Sun JC, Madera S, Bezman NA, Beilke JN, Kaplan MH, Lanier LL. 41.  2012. Proinflammatory cytokine signaling required for the generation of natural killer cell memory. J. Exp. Med. 209:5947–54 [Google Scholar]
  42. Sun JC, Beilke JN, Lanier LL. 42.  2009. Adaptive immune features of natural killer cells. Nature 457:7229557–61 Erratum 2009. Nature 457:72331168 [Google Scholar]
  43. Bendelac A, Savage PB, Teyton L. 43.  2007. The biology of NKT cells. Annu. Rev. Immunol. 25:297–336 [Google Scholar]
  44. Bendelac A, Rivera MN, Park SH, Roark JH. 44.  1997. Mouse CD1-specific NK1 T cells: development, specificity, and function. Annu. Rev. Immunol. 15:535–62 [Google Scholar]
  45. Matsuda JL, Naidenko OV, Gapin L, Nakayama T, Taniguchi M. 45.  et al. 2000. Tracking the response of natural killer T cells to a glycolipid antigen using CD1d tetramers. J. Exp. Med. 192:741–54 [Google Scholar]
  46. Dascher CC, Brenner MB. 46.  2003. Evolutionary constraints on CD1 structure: insights from comparative genomic analysis. Trends Immunol 24:412–18 [Google Scholar]
  47. Kenna T, Golden-Mason L, Porcelli SA, Koezuka Y, Hegarty JE. 47.  et al. 2003. NKT cells from normal and tumor-bearing human livers are phenotypically and functionally distinct from murine NKT cells. J. Immunol. 171:1775–79 [Google Scholar]
  48. Brossay L, Chioda M, Burdin N, Koezuka Y, Casorati G. 48.  et al. 1998. CD1d-mediated recognition of an alpha-galactosylceramide by natural killer T cells is highly conserved through mammalian evolution. J. Exp. Med. 188:1521–28 [Google Scholar]
  49. Arrenberg P, Halder R, Dai Y, Maricic I, Kumar V. 49.  2010. Oligoclonality and innate-like features in the TCR repertoire of type II NKT cells reactive to a beta-linked self-glycolipid. PNAS 107:10984–89 [Google Scholar]
  50. Blomqvist M, Rhost S, Teneberg S, Lofbom L, Osterbye T. 50.  et al. 2009. Multiple tissue-specific isoforms of sulfatide activate CD1d-restricted type II NKT cells. Eur. J. Immunol. 39:1726–35 [Google Scholar]
  51. Bendelac A. 51.  1995. Positive selection of mouse NK1+ T cells by CD1-expressing cortical thymocytes. J. Exp. Med. 182:2091–96 [Google Scholar]
  52. Benlagha K, Kyin T, Beavis A, Teyton L, Bendelac A. 52.  2002. A thymic precursor to the NK T cell lineage. Science 296:553–55 [Google Scholar]
  53. Dashtsoodol N, Shigeura T, Aihara M, Ozawa R, Kojo S. 53.  et al. 2017. Alternative pathway for the development of Vα14+ NKT cells directly from CD4CD8 thymocytes that bypasses the CD4+CD8+ stage. Nat. Immunol. 18:274–82 [Google Scholar]
  54. Gumperz JE, Miyake S, Yamamura T, Brenner MB. 54.  2002. Functionally distinct subsets of CD1d-restricted natural killer T cells revealed by CD1d tetramer staining. J. Exp. Med. 195:625–36 [Google Scholar]
  55. Kawano T, Cui J, Koezuka Y, Toura I, Kaneko Y. 55.  et al. 1998. Natural killer–like nonspecific tumor cell lysis mediated by specific ligand-activated Vα14 NKT cells. PNAS 95:5690–93 [Google Scholar]
  56. Constantinides MG, Bendelac A. 56.  2013. Transcriptional regulation of the NKT cell lineage. Curr. Opin. Immunol. 25:161–67 [Google Scholar]
  57. Lee PT, Benlagha K, Teyton L, Bendelac A. 57.  2002. Distinct functional lineages of human Vα24 natural killer T cells. J. Exp. Med. 195:637–41 [Google Scholar]
  58. Lee YJ, Wang H, Starrett GJ, Phuong V, Jameson SC, Hogquist KA. 58.  2015. Tissue-specific distribution of iNKT cells impacts their cytokine response. Immunity 43:566–78 [Google Scholar]
  59. DeAngelis RA, Markiewski MM, Kourtzelis I, Rafail S, Syriga M. 59.  et al. 2012. A complement-IL-4 regulatory circuit controls liver regeneration. J. Immunol. 188:641–48 [Google Scholar]
  60. Yin S, Wang H, Bertola A, Feng D, Xu MJ. 60.  et al. 2014. Activation of invariant natural killer T cells impedes liver regeneration by way of both IFN-γ- and IL-4-dependent mechanisms. Hepatology 60:1356–66 [Google Scholar]
  61. Park O, Jeong WI, Wang L, Wang H, Lian ZX. 61.  et al. 2009. Diverse roles of invariant natural killer T cells in liver injury and fibrosis induced by carbon tetrachloride. Hepatology 49:1683–94 [Google Scholar]
  62. Biburger M, Tiegs G. 62.  2005. α-Galactosylceramide-induced liver injury in mice is mediated by TNF-α but independent of Kupffer cells. J. Immunol. 175:1540–50 [Google Scholar]
  63. Wong CH, Jenne CN, Lee WY, Leger C, Kubes P. 63.  2011. Functional innervation of hepatic iNKT cells is immunosuppressive following stroke. Science 334:101–5 [Google Scholar]
  64. Georgiev H, Ravens I, Benarafa C, Forster R, Bernhardt G. 64.  2016. Distinct gene expression patterns correlate with developmental and functional traits of iNKT subsets. Nat. Commun. 7:13116 [Google Scholar]
  65. Anantha RV, Mazzuca DM, Xu SX, Porcelli SA, Fraser DD. 65.  et al. 2014. T helper type 2–polarized invariant natural killer T cells reduce disease severity in acute intra-abdominal sepsis. Clin. Exp. Immunol. 178:292–309 [Google Scholar]
  66. Bai L, Constantinides MG, Thomas SY, Reboulet R, Meng F. 66.  et al. 2012. Distinct APCs explain the cytokine bias of α-galactosylceramide variants in vivo. J. Immunol. 188:3053–61 [Google Scholar]
  67. Trobonjaca Z, Leithauser F, Moller P, Schirmbeck R, Reimann J. 67.  2001. Activating immunity in the liver. I. Liver dendritic cells (but not hepatocytes) are potent activators of IFN-γ release by liver NKT cells. J. Immunol. 167:1413–22 [Google Scholar]
  68. Stetson DB, Mohrs M, Reinhardt RL, Baron JL, Wang ZE. 68.  et al. 2003. Constitutive cytokine mRNAs mark natural killer (NK) and NK T cells poised for rapid effector function. J. Exp. Med. 198:1069–76 [Google Scholar]
  69. Geissmann F, Cameron TO, Sidobre S, Manlongat N, Kronenberg M. 69.  et al. 2005. Intravascular immune surveillance by CXCR6+ NKT cells patrolling liver sinusoids. PLOS Biol 3:e113 [Google Scholar]
  70. Campos RA, Szczepanik M, Lisbonne M, Itakura A, Leite-de-Moraes M, Askenase PW. 70.  2006. Invariant NKT cells rapidly activated via immunization with diverse contact antigens collaborate in vitro with B-1 cells to initiate contact sensitivity. J. Immunol. 177:3686–94 [Google Scholar]
  71. Campos RA, Szczepanik M, Itakura A, Kahira-Azuma M, Sidobre S. 71.  et al. 2003. Cutaneous immunization rapidly activates liver invariant Vα14 NKT cells stimulating B-1 B cells to initiate T cell recruitment for elicitation of contact sensitivity. J. Exp. Med. 198:1785–96 [Google Scholar]
  72. Velazquez P, Cameron TO, Kinjo Y, Nagarajan N, Kronenberg M, Dustin ML. 72.  2008. Cutting edge: Activation by innate cytokines or microbial antigens can cause arrest of natural killer T cell patrolling of liver sinusoids. J. Immunol. 180:2024–28 [Google Scholar]
  73. Liew PX, Lee W-Y, Kubes P. 73.  2017. iNKT cells orchestrate a switch from inflammation to resolution of sterile liver injury. Immunity 47:752–65.e5 [Google Scholar]
  74. Petri B, Phillipson M, Kubes P. 74.  2008. The physiology of leukocyte recruitment: an in vivo perspective. J. Immunol. 180:6439–46 [Google Scholar]
  75. Ley K, Laudanna C, Cybulsky MI, Nourshargh S. 75.  2007. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat. Rev. Immunol. 7:678–89 [Google Scholar]
  76. Beste MT, Hammer DA. 76.  2008. Selectin catch-slip kinetics encode shear threshold adhesive behavior of rolling leukocytes. PNAS 105:20716–21 [Google Scholar]
  77. McDonald B, McAvoy EF, Lam F, Gill V, de la Motte C. 77.  et al. 2008. Interaction of CD44 and hyaluronan is the dominant mechanism for neutrophil sequestration in inflamed liver sinusoids. J. Exp. Med. 205:915–27 [Google Scholar]
  78. Fox-Robichaud A, Kubes P. 78.  2000. Molecular mechanisms of tumor necrosis factor α–stimulated leukocyte recruitment into the hepatic circulation. Hepatology 31:1123–27 [Google Scholar]
  79. Wong J, Johnston B, Lee SS, Bullard DC, Smith CW. 79.  et al. 1997. A minimal role for selectins in the recruitment of leukocytes into the inflamed liver microvasculature. J. Clin. Investig. 99:2782–90 [Google Scholar]
  80. Kivi E, Elima K, Aalto K, Nymalm Y, Auvinen K. 80.  et al. 2009. Human Siglec-10 can bind to vascular adhesion protein-1 and serves as its substrate. Blood 114:5385–92 [Google Scholar]
  81. Aalto K, Autio A, Kiss EA, Elima K, Nymalm Y. 81.  et al. 2011. Siglec-9 is a novel leukocyte ligand for vascular adhesion protein-1 and can be used in PET imaging of inflammation and cancer. Blood 118:3725–33 [Google Scholar]
  82. Ichida T, Sugitani S, Satoh T, Matsuda Y, Sugiyama M. 82.  et al. 1996. Localization of hyaluronan in human liver sinusoids: a histochemical study using hyaluronan-binding protein. Liver 16:365–71 [Google Scholar]
  83. Jackson DG. 83.  2004. Biology of the lymphatic marker LYVE-1 and applications in research into lymphatic trafficking and lymphangiogenesis. APMIS 112:526–38 [Google Scholar]
  84. Falkowski M, Schledzewski K, Hansen B, Goerdt S. 84.  2003. Expression of stabilin-2, a novel fasciclin-like hyaluronan receptor protein, in murine sinusoidal endothelia, avascular tissues, and at solid/liquid interfaces. Histochem. Cell Biol. 120:361–69 [Google Scholar]
  85. McDonald B, Kubes P. 85.  2015. Interactions between CD44 and hyaluronan in leukocyte trafficking. Front. Immunol. 6:68 [Google Scholar]
  86. Zhuo L, Kanamori A, Kannagi R, Itano N, Wu J. 86.  et al. 2006. SHAP potentiates the CD44-mediated leukocyte adhesion to the hyaluronan substratum. J. Biol. Chem. 281:20303–14 [Google Scholar]
  87. McAvoy E, McDonald B, Kubes P. 87.  2007. The adhesion molecules CD44 and hyaluronan, not physical trapping, are responsible for neutrophil sequestration in inflamed liver sinusoids. J. Immunol. 178:1 Suppl.S189–90 (Abstr.) [Google Scholar]
  88. Menezes GB, Lee WY, Zhou H, Waterhouse CC, Cara DC, Kubes P. 88.  2009. Selective down-regulation of neutrophil Mac-1 in endotoxemic hepatic microcirculation via IL-10. J. Immunol. 183:7557–68 [Google Scholar]
  89. Mohamadzadeh M, DeGrendele H, Arizpe H, Estess P, Siegelman M. 89.  1998. Proinflammatory stimuli regulate endothelial hyaluronan expression and CD44/HA-dependent primary adhesion. J. Clin. Investig. 101:97–108 [Google Scholar]
  90. Day AJ, de la Motte CA. 90.  2005. Hyaluronan cross-linking: a protective mechanism in inflammation?. Trends Immunol 26:637–43 [Google Scholar]
  91. de la Motte CA, Hascall VC, Drazba J, Bandyopadhyay SK, Strong SA. 91.  2003. Mononuclear leukocytes bind to specific hyaluronan structures on colon mucosal smooth muscle cells treated with polyinosinic acid:polycytidylic acid: Inter-α-trypsin inhibitor is crucial to structure and function. Am. J. Pathol. 163:121–33 [Google Scholar]
  92. Shi C, Velazquez P, Hohl TM, Leiner I, Dustin ML, Pamer EG. 92.  2010. Monocyte trafficking to hepatic sites of bacterial infection is chemokine independent and directed by focal intercellular adhesion molecule-1 expression. J. Immunol. 184:6266–74 [Google Scholar]
  93. McDonald B, Urrutia R, Yipp BG, Jenne CN, Kubes P. 93.  2012. Intravascular neutrophil extracellular traps capture bacteria from the bloodstream during sepsis. Cell Host Microbe 12:324–33 [Google Scholar]
  94. Jenne CN, Wong CH, Zemp FJ, McDonald B, Rahman MM. 94.  et al. 2013. Neutrophils recruited to sites of infection protect from virus challenge by releasing neutrophil extracellular traps. Cell Host Microbe 13:169–80 [Google Scholar]
  95. Kimura K, Nagaki M, Saio M, Moriwaki H, Kakimi K. 95.  2009. Role of CD44 in CTL-induced acute liver injury in hepatitis B virus transgenic mice. J. Gastroenterol. 44:218–27 [Google Scholar]
  96. Younossi ZM, Stepanova M, Afendy M, Fang Y, Younossi Y. 96.  et al. 2011. Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clin. Gastroenterol. Hepatol. 9:524–30 [Google Scholar]
  97. Egan CE, Daugherity EK, Rogers AB, Abi Abdallah DS, Denkers EY, Maurer KJ. 97.  2013. CCR2 and CD44 promote inflammatory cell recruitment during fatty liver formation in a lithogenic diet fed mouse model. PLOS ONE 8:e65247 [Google Scholar]
  98. Kang HS, Liao G, DeGraff LM, Gerrish K, Bortner CD. 98.  et al. 2013. CD44 plays a critical role in regulating diet-induced adipose inflammation, hepatic steatosis, and insulin resistance. PLOS ONE 8:e58417 [Google Scholar]
  99. Bonder CS, Norman MU, Swain MG, Zbytnuik LD, Yamanouchi J. 99.  et al. 2005. Rules of recruitment for Th1 and Th2 lymphocytes in inflamed liver: a role for α-4 integrin and vascular adhesion protein-1. Immunity 23:153–63 [Google Scholar]
  100. Lalor PF, Edwards S, McNab G, Salmi M, Jalkanen S, Adams DH. 100.  2002. Vascular adhesion protein-1 mediates adhesion and transmigration of lymphocytes on human hepatic endothelial cells. J. Immunol. 169:983–92 [Google Scholar]
  101. Kurkijarvi R, Adams DH, Leino R, Mottonen T, Jalkanen S, Salmi M. 101.  1998. Circulating form of human vascular adhesion protein-1 (VAP-1): increased serum levels in inflammatory liver diseases. J. Immunol. 161:1549–57 [Google Scholar]
  102. Trivedi PJ, Tickle J, Vesterhus MN, Eddowes PJ, Bruns T. 102.  et al. 2017. Vascular adhesion protein-1 is elevated in primary sclerosing cholangitis, is predictive of clinical outcome and facilitates recruitment of gut-tropic lymphocytes to liver in a substrate-dependent manner. Gut In press. https://doi.org/10.1136/gutjnl-2016-312354 [Crossref]
  103. Tanaka S, Tanaka T, Kawakami T, Takano H, Sugahara M. 103.  et al. 2017. Vascular adhesion protein-1 enhances neutrophil infiltration by generation of hydrogen peroxide in renal ischemia/reperfusion injury. Kidney Int 92:154–64 [Google Scholar]
  104. Weston CJ, Shepherd EL, Claridge LC, Rantakari P, Curbishley SM. 104.  et al. 2015. Vascular adhesion protein-1 promotes liver inflammation and drives hepatic fibrosis. J. Clin. Investig. 125:501–20 [Google Scholar]
  105. Zhang J, Xu P, Song P, Wang H, Zhang Y. 105.  et al. 2016. CCL2-CCR2 signaling promotes hepatic ischemia/reperfusion injury. J. Surg. Res. 202:352–62 [Google Scholar]
  106. Mossanen JC, Krenkel O, Ergen C, Govaere O, Liepelt A. 106.  et al. 2016. Chemokine (C-C motif) receptor 2–positive monocytes aggravate the early phase of acetaminophen-induced acute liver injury. Hepatology 64:1667–82 [Google Scholar]
  107. Krenkel O, Tacke F. 107.  2017. Liver macrophages in tissue homeostasis and disease. Nat. Rev. Immunol. 17:306–21 [Google Scholar]
  108. Auffray C, Fogg D, Garfa M, Elain G, Join-Lambert O. 108.  et al. 2007. Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science 317:666–70 [Google Scholar]
  109. Carlin LM, Stamatiades EG, Auffray C, Hanna RN, Glover L. 109.  et al. 2013. Nr4a1-dependent Ly6Clow monocytes monitor endothelial cells and orchestrate their disposal. Cell 153:362–75 [Google Scholar]
  110. Dal-Secco D, Wang J, Zeng Z, Kolaczkowska E, Wong CH. 110.  et al. 2015. A dynamic spectrum of monocytes arising from the in situ reprogramming of CCR2+ monocytes at a site of sterile injury. J. Exp. Med. 212:447–56 [Google Scholar]
  111. Reid DT, Reyes JL, McDonald BA, Vo T, Reimer RA, Eksteen B. 111.  2016. Kupffer cells undergo fundamental changes during the development of experimental NASH and are critical in initiating liver damage and inflammation. PLOS ONE 11:e0159524 [Google Scholar]
  112. Wang M, You Q, Lor K, Chen F, Gao B, Ju C. 112.  2014. Chronic alcohol ingestion modulates hepatic macrophage populations and functions in mice. J. Leukoc. Biol. 96:657–65 [Google Scholar]
  113. Lefebvre E, Moyle G, Reshef R, Richman LP, Thompson M. 113.  et al. 2016. Antifibrotic effects of the dual CCR2/CCR5 antagonist cenicriviroc in animal models of liver and kidney fibrosis. PLOS ONE 11:e0158156 [Google Scholar]
  114. Friedman S, Sanyal A, Goodman Z, Lefebvre E, Gottwald M. 114.  et al. 2016. Efficacy and safety study of cenicriviroc for the treatment of non-alcoholic steatohepatitis in adult subjects with liver fibrosis: CENTAUR Phase 2b study design. Contemp. Clin. Trials 47:356–65 [Google Scholar]
  115. Wang J, Kubes P. 115.  2016. A reservoir of mature cavity macrophages that can rapidly invade visceral organs to affect tissue repair. Cell 165:668–78 [Google Scholar]
  116. Durand F, Francoz C. 116.  2017. The future of liver transplantation for viral hepatitis. Liver Int 37:Suppl. 1130–35 [Google Scholar]
  117. Wong YC, McCaughan GW, Bowen DG, Bertolino P. 117.  2016. The CD8 T-cell response during tolerance induction in liver transplantation. Clin. Transl. Immunol. 5:e102 [Google Scholar]
  118. Fahrner R, Dondorf F, Ardelt M, Settmacher U, Rauchfuss F. 118.  2016. Role of NK, NKT cells and macrophages in liver transplantation. World J. Gastroenterol. 22:6135–44 [Google Scholar]
  119. Protzer U, Maini MK, Knolle PA. 119.  2012. Living in the liver: hepatic infections. Nat. Rev. Immunol. 12:201–13 [Google Scholar]
  120. Maini MK, Gehring AJ. 120.  2016. The role of innate immunity in the immunopathology and treatment of HBV infection. J. Hepatol. 64:S60–70 [Google Scholar]
  121. Dustin LB, Cashman SB, Laidlaw SM. 121.  2014. Immune control and failure in HCV infection: tipping the balance. J. Leukoc. Biol. 96:535–48 [Google Scholar]
  122. Qian S, Wang Z, Lee Y, Chiang Y, Bonham C, Fung J, Lu L. 122.  2001. Hepatocyte-induced apoptosis of activated T cells, a mechanism of liver transplant tolerance, is related to the expression of ICAM-1 and hepatic lectin. Transplant. Proc. 33:226 [Google Scholar]
  123. Bertolino P, McCaughan GW, Bowen DG. 123.  2002. Role of primary intrahepatic T-cell activation in the ‘liver tolerance effect’. Immunol. Cell Biol. 80:84–92 [Google Scholar]
  124. Wahl C, Bochtler P, Chen L, Schirmbeck R, Reimann J. 124.  2008. B7-H1 on hepatocytes facilitates priming of specific CD8 T cells but limits the specific recall of primed responses. Gastroenterology 135:980–88 [Google Scholar]
  125. Knolle PA, Uhrig A, Hegenbarth S, Loser E, Schmitt E. 125.  et al. 1998. IL-10 down-regulates T cell activation by antigen-presenting liver sinusoidal endothelial cells through decreased antigen uptake via the mannose receptor and lowered surface expression of accessory molecules. Clin. Exp. Immunol. 114:427–33 [Google Scholar]
  126. Pillarisetty VG, Shah AB, Miller G, Bleier JI, DeMatteo RP. 126.  2004. Liver dendritic cells are less immunogenic than spleen dendritic cells because of differences in subtype composition. J. Immunol. 172:1009–17 [Google Scholar]
  127. Tokita D, Sumpter TL, Raimondi G, Zahorchak AF, Wang Z. 127.  et al. 2008. Poor allostimulatory function of liver plasmacytoid DC is associated with pro-apoptotic activity, dependent on regulatory T cells. J. Hepatol. 49:1008–18 [Google Scholar]
  128. Sana G, Lombard C, Vosters O, Jazouli N, Andre F. 128.  et al. 2013. Adult human hepatocytes promote CD4+ T cell hyporesponsiveness via interleukin-10 producing allogeneic dendritic cells. Cell Transplant 23:1127–42 [Google Scholar]
  129. Knolle PA, Germann T, Treichel U, Uhrig A, Schmitt E. 129.  et al. 1999. Endotoxin down-regulates T cell activation by antigen-presenting liver sinusoidal endothelial cells. J. Immunol. 162:1401–7 [Google Scholar]
  130. Diehl L, Schurich A, Grochtmann R, Hegenbarth S, Chen L, Knolle PA. 130.  2008. Tolerogenic maturation of liver sinusoidal endothelial cells promotes B7-homolog 1–dependent CD8+ T cell tolerance. Hepatology 47:296–305 [Google Scholar]
  131. Berg M, Wingender G, Djandji D, Hegenbarth S, Momburg F. 131.  et al. 2006. Cross-presentation of antigens from apoptotic tumor cells by liver sinusoidal endothelial cells leads to tumor-specific CD8+ T cell tolerance. Eur. J. Immunol. 36:2960–70 [Google Scholar]
  132. Limmer A, Ohl J, Wingender G, Berg M, Jungerkes F. 132.  et al. 2005. Cross-presentation of oral antigens by liver sinusoidal endothelial cells leads to CD8 T cell tolerance. Eur. J. Immunol. 35:2970–81 [Google Scholar]
  133. Limmer A, Ohl J, Kurts C, Ljunggren HG, Reiss Y. 133.  et al. 2000. Efficient presentation of exogenous antigen by liver endothelial cells to CD8+ T cells results in antigen-specific T-cell tolerance. Nat. Med. 6:1348–54 [Google Scholar]
  134. Racanelli V, Rehermann B. 134.  2006. The liver as an immunological organ. Hepatology 43:S54–62 [Google Scholar]
  135. Seki E, Brenner DA. 135.  2008. Toll-like receptors and adaptor molecules in liver disease: update. Hepatology 48:322–35 [Google Scholar]
  136. Zhang X, Meng Z, Qiu S, Xu Y, Yang D. 136.  et al. 2009. Lipopolysaccharide-induced innate immune responses in primary hepatocytes downregulates woodchuck hepatitis virus replication via interferon-independent pathways. Cell Microbiol 11:1624–37 [Google Scholar]
  137. Franco A, Barnaba V, Natali P, Balsano C, Musca A, Balsano F. 137.  1988. Expression of class I and class II major histocompatibility complex antigens on human hepatocytes. Hepatology 8:449–54 [Google Scholar]
  138. Chen M, Tabaczewski P, Truscott SM, Van Kaer L, Stroynowski I. 138.  2005. Hepatocytes express abundant surface class I MHC and efficiently use transporter associated with antigen processing, tapasin, and low molecular weight polypeptide proteasome subunit components of antigen processing and presentation pathway. J. Immunol. 175:1047–55 [Google Scholar]
  139. Warren A, Le Couteur DG, Fraser R, Bowen DG, McCaughan GW, Bertolino P. 139.  2006. T lymphocytes interact with hepatocytes through fenestrations in murine liver sinusoidal endothelial cells. Hepatology 44:1182–90 [Google Scholar]
  140. Balam S, Romero JF, Bongfen SE, Guillaume P, Corradin G. 140.  2012. CSP—a model for in vivo presentation of Plasmodium berghei sporozoite antigens by hepatocytes. PLOS ONE 7:e51875 [Google Scholar]
  141. Bertolino P, Bowen DG, McCaughan GW, Fazekas de St Groth B. 141.  2001. Antigen-specific primary activation of CD8+ T cells within the liver. J. Immunol. 166:5430–38 [Google Scholar]
  142. Guidotti LG, Inverso D, Sironi L, Di Lucia P, Fioravanti J. 142.  et al. 2015. Immunosurveillance of the liver by intravascular effector CD8+ T cells. Cell 161:486–500 [Google Scholar]
  143. Crispe IN. 143.  2011. Liver antigen-presenting cells. J. Hepatol. 54:357–65 [Google Scholar]
  144. Parker GA, Picut CA. 144.  2005. Liver immunobiology. Toxicol. Pathol. 33:52–62 [Google Scholar]
  145. Sato T, Yamamoto H, Sasaki C, Wake K. 145.  1998. Maturation of rat dendritic cells during intrahepatic translocation evaluated using monoclonal antibodies and electron microscopy. Cell Tissue Res 294:503–14 [Google Scholar]
  146. Kudo S, Matsuno K, Ezaki T, Ogawa M. 146.  1997. A novel migration pathway for rat dendritic cells from the blood: hepatic sinusoids–lymph translocation. J. Exp. Med. 185:777–84 [Google Scholar]
  147. Pillarisetty VG, Katz SC, Bleier JI, Shah AB, DeMatteo RP. 147.  2005. Natural killer dendritic cells have both antigen presenting and lytic function and in response to CpG produce IFN-γ via autocrine IL-12. J. Immunol. 174:2612–18 [Google Scholar]
  148. Doherty DG. 148.  2016. Immunity, tolerance and autoimmunity in the liver: a comprehensive review. J. Autoimmun. 66:60–75 [Google Scholar]
  149. Goddard S, Youster J, Morgan E, Adams DH. 149.  2004. Interleukin-10 secretion differentiates dendritic cells from human liver and skin. Am. J. Pathol. 164:511–19 [Google Scholar]
  150. Gao X, Wang S, Fan Y, Bai H, Yang J, Yang X. 150.  2010. CD8+ DC, but not CD8 DC, isolated from BCG-infected mice reduces pathological reactions induced by mycobacterial challenge infection. PLOS ONE 5:e9281 [Google Scholar]
  151. Heymann F, Tacke F. 151.  2016. Immunology in the liver—from homeostasis to disease. Nat. Rev. Gastroenterol. Hepatol. 13:88–110 [Google Scholar]
  152. Chen L, Calomeni E, Wen J, Ozato K, Shen R, Gao JX. 152.  2007. Natural killer dendritic cells are an intermediate of developing dendritic cells. J. Leukoc. Biol. 81:1422–33 [Google Scholar]
  153. Kingham TP, Chaudhry UI, Plitas G, Katz SC, Raab J, DeMatteo RP. 153.  2007. Murine liver plasmacytoid dendritic cells become potent immunostimulatory cells after Flt-3 ligand expansion. Hepatology 45:445–54 [Google Scholar]
  154. Abo T, Kawamura T, Watanabe H. 154.  2000. Physiological responses of extrathymic T cells in the liver. Immunol. Rev. 174:135–49 [Google Scholar]
  155. Inverso D, Iannacone M. 155.  2016. Spatiotemporal dynamics of effector CD8+ T cell responses within the liver. J. Leukoc. Biol. 99:51–55 [Google Scholar]
  156. Benechet AP, Iannacone M. 156.  2016. Determinants of hepatic effector CD8+ T cell dynamics. J. Hepatol. 66:228–33 [Google Scholar]
  157. Wang L, Wang K, Zou ZQ. 157.  2015. Crosstalk between innate and adaptive immunity in hepatitis B virus infection. World J. Hepatol. 7:2980–91 [Google Scholar]
  158. Shuai Z, Leung MW, He X, Zhang W, Yang G. 158.  et al. 2016. Adaptive immunity in the liver. Cell. Mol. Immunol. 13:354–68 [Google Scholar]
  159. Zamor PJ, deLemos AS, Russo MW. 159.  2017. Viral hepatitis and hepatocellular carcinoma: etiology and management. J. Gastrointest. Oncol. 8:229–42 [Google Scholar]
  160. Cholankeril G, Patel R, Khurana S, Satapathy SK. 160.  2017. Hepatocellular carcinoma in non-alcoholic steatohepatitis: current knowledge and implications for management. World J. Hepatol. 9:533–43 [Google Scholar]
  161. Balogh J, Victor D III, Asham EH, Burroughs SG, Boktour M. 161.  et al. 2016. Hepatocellular carcinoma: a review. J. Hepatocell. Carcinoma 3:41–53 [Google Scholar]
  162. Ghouri YA, Mian I, Rowe JH. 162.  2017. Review of hepatocellular carcinoma: epidemiology, etiology, and carcinogenesis. J. Carcinog. 16:1 [Google Scholar]
  163. Zhang B, Han S, Feng B, Chu X, Chen L, Wang R. 163.  2017. Hepatitis B virus X protein–mediated non-coding RNA aberrations in the development of human hepatocellular carcinoma. Exp. Mol. Med. 49:e293 [Google Scholar]
  164. Jin K, Li T, Sanchez-Duffhues G, Zhou F, Zhang L. 164.  2017. Involvement of inflammation and its related microRNAs in hepatocellular carcinoma. Oncotarget 8:22145–65 [Google Scholar]
  165. Ahmed A, Wong RJ, Harrison SA. 165.  2015. Nonalcoholic fatty liver disease review: diagnosis, treatment, and outcomes. Clin. Gastroenterol. Hepatol. 13:2062–70 [Google Scholar]
  166. van der Poorten D, Milner KL, Hui J, Hodge A, Trenell MI. 166.  et al. 2008. Visceral fat: a key mediator of steatohepatitis in metabolic liver disease. Hepatology 48:449–57 [Google Scholar]
  167. Kubes P, Mehal WZ. 167.  2012. Sterile inflammation in the liver. Gastroenterology 143:1158–72 [Google Scholar]
  168. Baumert TF, Juhling F, Ono A, Hoshida Y. 168.  2017. Hepatitis C–related hepatocellular carcinoma in the era of new generation antivirals. BMC Med 15:52 [Google Scholar]
  169. Ponziani FR, Mangiola F, Binda C, Zocco MA, Siciliano M. 169.  et al. 2017. Future of liver disease in the era of direct acting antivirals for the treatment of hepatitis C. World J. Hepatol. 9:352–67 [Google Scholar]
  170. Tahmasebi BM, Carloni V. 170.  2017. Tumor microenvironment, a paradigm in hepatocellular carcinoma progression and therapy. Int. J. Mol. Sci. 18:405 [Google Scholar]
  171. Fukuhara H, Ino Y, Todo T. 171.  2016. Oncolytic virus therapy: a new era of cancer treatment at dawn. Cancer Sci 107:1373–79 [Google Scholar]
  172. Jones RP, Kokudo N, Folprecht G, Mise Y, Unno M. 172.  et al. 2016. Colorectal liver metastases: a critical review of state of the art. Liver Cancer 6:66–71 [Google Scholar]
  173. Clark AM, Ma B, Taylor DL, Griffith L, Wells A. 173.  2016. Liver metastases: microenvironments and ex-vivo models. Exp. Biol. Med. 241:1639–52 [Google Scholar]
  174. Vatandoust S, Price TJ, Karapetis CS. 174.  2015. Colorectal cancer: metastases to a single organ. World J. Gastroenterol. 21:11767–76 [Google Scholar]
  175. Itatani Y, Kawada K, Inamoto S, Yamamoto T, Ogawa R. 175.  et al. 2016. The role of chemokines in promoting colorectal cancer invasion/metastasis. Int. J. Mol. Sci. 17:643 [Google Scholar]
  176. McDonald B, Spicer J, Giannais B, Fallavollita L, Brodt P, Ferri LE. 176.  2009. Systemic inflammation increases cancer cell adhesion to hepatic sinusoids by neutrophil mediated mechanisms. Int. J. Cancer 125:1298–305 [Google Scholar]
  177. Spicer JD, McDonald B, Cools-Lartigue JJ, Chow SC, Giannias B. 177.  et al. 2012. Neutrophils promote liver metastasis via Mac-1-mediated interactions with circulating tumor cells. Cancer Res 72:3919–27 [Google Scholar]
  178. Cools-Lartigue J, Spicer J, McDonald B, Gowing S, Chow S. 178.  et al. 2013. Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis. J. Clin. Investig. 123:3446–58 [Google Scholar]
  179. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y. 179.  et al. 2004. Neutrophil extracellular traps kill bacteria. Science 303:1532–35 [Google Scholar]
  180. Slaba I, Wang J, Kolaczkowska E, McDonald B, Lee WY, Kubes P. 180.  2015. Imaging the dynamic platelet-neutrophil response in sterile liver injury and repair in mice. Hepatology 62:1593–605 [Google Scholar]
  181. Wang J, Hossain M, Thanabalasuriar A, Gunzer M, Meininger C, Kubes P. 180a.  2017. Visualizing the function and fate of neutrophils in sterile injury and repair. Science 358:6359111–16 [Google Scholar]
  182. Woolbright BL, Jaeschke H. 181.  2017. The impact of sterile inflammation in acute liver injury. J. Clin. Transl. Res. 3:170–88 [Google Scholar]
  183. Kuboki S, Shin T, Huber N, Eismann T, Galloway E. 182.  et al. 2008. Hepatocyte signaling through CXC chemokine receptor-2 is detrimental to liver recovery after ischemia/reperfusion in mice. Hepatology 48:1213–23 [Google Scholar]
  184. Kubes P, Payne D, Woodman RC. 183.  2002. Molecular mechanisms of leukocyte recruitment in postischemic liver microcirculation. Am. J. Physiol. Gastrointest. Liver Physiol. 283:G139–47 [Google Scholar]
  185. Jaeschke H, McGill MR, Williams CD. 184.  2013. Pathophysiological relevance of neutrophils in acetaminophen hepatotoxicity. Hepatology 57:419 [Google Scholar]
  186. Bertola A, Park O, Gao B. 185.  2013. Chronic plus binge ethanol feeding synergistically induces neutrophil infiltration and liver injury in mice: a critical role for E-selectin. Hepatology 58:1814–23 [Google Scholar]
  187. Gao B, Xu MJ, Bertola A, Wang H, Zhou Z, Liangpunsakul S. 186.  2017. Animal models of alcoholic liver disease: pathogenesis and clinical relevance. Gene Expr 17:173–86 [Google Scholar]
  188. Zang S, Wang L, Ma X, Zhu G, Zhuang Z. 187.  et al. 2015. Neutrophils play a crucial role in the early stage of nonalcoholic steatohepatitis via neutrophil elastase in mice. Cell Biochem. Biophys. 73:479–87 [Google Scholar]

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error