Review Article | Published:

Liver sinusoidal endothelial cells — gatekeepers of hepatic immunity

Nature Reviews Gastroenterology & Hepatology (2018) | Download Citation

Abstract

Liver sinusoidal endothelial cells (LSECs) line the low shear, sinusoidal capillary channels of the liver and are the most abundant non-parenchymal hepatic cell population. LSECs do not simply form a barrier within the hepatic sinusoids but have vital physiological and immunological functions, including filtration, endocytosis, antigen presentation and leukocyte recruitment. Reflecting these multifunctional properties, LSECs display unique structural and phenotypic features that differentiate them from the capillary endothelium present within other organs. It is now clear that LSECs have a critical role in maintaining immune homeostasis within the liver and in mediating the immune response during acute and chronic liver injury. In this Review, we outline how LSECs influence the immune microenvironment within the liver and discuss their contribution to immune-mediated liver diseases and the complications of fibrosis and carcinogenesis.

Key points

  • Liver sinusoidal endothelial cells (LSECs) that line the hepatic sinusoids have important physiological roles and mediate the filtration and scavenger functions of the liver.

  • LSECs also have innate and adaptive immunological functions, including antigen presentation and maintenance of the balance between tolerance and effector immune responses.

  • In inflammatory liver diseases, LSECs influence the composition of hepatic immune populations by mediating diapedesis of leukocyte subsets via distinct combinations of adhesion molecules and chemokines.

  • LSECs play a crucial part in the cellular crosstalk that regulates progressive chronic liver disease, which leads to fibrosis and carcinogenesis.

  • The role of LSECs in initiating immune responses and contributing to progressive liver disease makes them a potential therapeutic target for treating inflammatory liver diseases.

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References

  1. 1.

    Sorensen, K. K., Simon-Santamaria, J., McCuskey, R. S. & Smedsrod, B. Liver sinusoidal endothelial cells. Compr. Physiol. 5, 1751–1774 (2015).

  2. 2.

    Poisson, J. et al. Liver sinusoidal endothelial cells: physiology and role in liver diseases. J. Hepatol. 66, 212–227 (2017).

  3. 3.

    Mates, J. M. et al. Mouse liver sinusoidal endothelium eliminates HIV-like particles from blood at a rate of 100 million per minute by a second-order kinetic process. Front. Immunol. 8, 35 (2017).

  4. 4.

    Smedsrod, B. Clearance function of scavenger endothelial cells. Comp. Hepatol. 3 (Suppl. 1), S22 (2004).

  5. 5.

    Li, R. et al. Role of liver sinusoidal endothelial cells and stabilins in elimination of oxidized low-density lipoproteins. Am. J. Physiol. Gastrointest. Liver Physiol. 300, G71–G81 (2011).

  6. 6.

    Potente, M. & Makinen, T. Vascular heterogeneity and specialization in development and disease. Nat. Rev. Mol. Cell Biol. 18, 477–494 (2017).

  7. 7.

    Gouysse, G. et al. Relationship between vascular development and vascular differentiation during liver organogenesis in humans. J. Hepatol. 37, 730–740 (2002).

  8. 8.

    Geraud, C. et al. GATA4-dependent organ-specific endothelial differentiation controls liver development and embryonic hematopoiesis. J. Clin. Invest. 127, 1099–1114 (2017).

  9. 9.

    Lalor, P. F., Lai, W. K., Curbishley, S. M., Shetty, S. & Adams, D. H. Human hepatic sinusoidal endothelial cells can be distinguished by expression of phenotypic markers related to their specialised functions in vivo. World J. Gastroenterol. 12, 5429–5439 (2006).

  10. 10.

    Geraud, C. et al. Unique cell type-specific junctional complexes in vascular endothelium of human and rat liver sinusoids. PLoS ONE 7, e34206 (2012).

  11. 11.

    Choi, Y. K., Fallert Junecko, B. A., Klamar, C. R. & Reinhart, T. A. Characterization of cells expressing lymphatic marker LYVE-1 in macaque large intestine during simian immunodeficiency virus infection identifies a large population of nonvascular LYVE-1(+)/DC-SIGN(+) cells. Lymphat Res. Biol. 11, 26–34 (2013).

  12. 12.

    Tanaka, M. & Iwakiri, Y. The hepatic lymphatic vascular system: structure, function, markers, and lymphangiogenesis. Cell. Mol. Gastroenterol. Hepatol. 2, 733–749 (2016).

  13. 13.

    Yokomori, H. et al. Lymphatic marker podoplanin/D2-40 in human advanced cirrhotic liver — re-evaluations of microlymphatic abnormalities. BMC Gastroenterol. 10, 131 (2010).

  14. 14.

    Lai, W. K. et al. Expression of DC-SIGN and DC-SIGNR on human sinusoidal endothelium: a role for capturing hepatitis C virus particles. Am. J. Pathol. 169, 200–208 (2006).

  15. 15.

    Strauss, O., Phillips, A., Ruggiero, K., Bartlett, A. & Dunbar, P. R. Immunofluorescence identifies distinct subsets of endothelial cells in the human liver. Sci. Rep. 7, 44356 (2017).

  16. 16.

    Milici, A. J., L’Hernault, N. & Palade, G. E. Surface densities of diaphragmed fenestrae and transendothelial channels in different murine capillary beds. Circ. Res. 56, 709–717 (1985).

  17. 17.

    Satchell, S. C. & Braet, F. Glomerular endothelial cell fenestrations: an integral component of the glomerular filtration barrier. Am. J. Physiol. Renal Physiol. 296, F947–F956 (2009).

  18. 18.

    Steiniger, B. S. Human spleen microanatomy: why mice do not suffice. Immunology 145, 334–346 (2015).

  19. 19.

    Bautz, F., Rafii, S., Kanz, L. & Mohle, R. Expression and secretion of vascular endothelial growth factor-A by cytokine-stimulated hematopoietic progenitor cells. Possible role in the hematopoietic microenvironment. Exp. Hematol. 28, 700–706 (2000).

  20. 20.

    Hashizume, H. et al. Openings between defective endothelial cells explain tumor vessel leakiness. Am. J. Pathol. 156, 1363–1380 (2000).

  21. 21.

    DeLeve, L. D. Liver sinusoidal endothelial cells in hepatic fibrosis. Hepatology 61, 1740–1746 (2015).

  22. 22.

    Mak, K. M. & Lieber, C. S. Alterations in endothelial fenestrations in liver sinusoids of baboons fed alcohol: a scanning electron microscopic study. Hepatology 4, 386–391 (1984).

  23. 23.

    Cogger, V. C. et al. Dietary macronutrients and the aging liver sinusoidal endothelial cell. Am. J. Physiol. Heart Circ. Physiol. 310, H1064–H1070 (2016).

  24. 24.

    O’Reilly, J. N., Cogger, V. C., Fraser, R. & Le Couteur, D. G. The effect of feeding and fasting on fenestrations in the liver sinusoidal endothelial cell. Pathology 42, 255–258 (2010).

  25. 25.

    Jamieson, H. A. et al. Caloric restriction reduces age-related pseudocapillarization of the hepatic sinusoid. Exp. Gerontol. 42, 374–378 (2007).

  26. 26.

    Svistounov, D. et al. The relationship between fenestrations, sieve plates and rafts in liver sinusoidal endothelial cells. PLoS ONE 7, e46134 (2012).

  27. 27.

    Protzer, U., Maini, M. K. & Knolle, P. A. Living in the liver: hepatic infections. Nat. Rev. Immunol. 12, 201–213 (2012).

  28. 28.

    Braet, F. & Wisse, E. Structural and functional aspects of liver sinusoidal endothelial cell fenestrae: a review. Comp. Hepatol. 1, 1 (2002).

  29. 29.

    Monkemoller, V., Oie, C., Hubner, W., Huser, T. & McCourt, P. Multimodal super-resolution optical microscopy visualizes the close connection between membrane and the cytoskeleton in liver sinusoidal endothelial cell fenestrations. Sci. Rep. 5, 16279 (2015).

  30. 30.

    Braet, F. et al. Three-dimensional organization of fenestrae labyrinths in liver sinusoidal endothelial cells. Liver Int. 29, 603–613 (2009).

  31. 31.

    Chen, G. Y. & Nunez, G. Sterile inflammation: sensing and reacting to damage. Nat. Rev. Immunol. 10, 826–837 (2010).

  32. 32.

    Uhrig, A. et al. Development and functional consequences of LPS tolerance in sinusoidal endothelial cells of the liver. J. Leukoc. Biol. 77, 626–633 (2005).

  33. 33.

    Wu, J. et al. Toll-like receptor-induced innate immune responses in non-parenchymal liver cells are cell type-specific. Immunology 129, 363–374 (2010).

  34. 34.

    Canton, J., Neculai, D. & Grinstein, S. Scavenger receptors in homeostasis and immunity. Nat. Rev. Immunol. 13, 621–634 (2013).

  35. 35.

    Elvevold, K. et al. Liver sinusoidal endothelial cells depend on mannose receptor-mediated recruitment of lysosomal enzymes for normal degradation capacity. Hepatology 48, 2007–2015 (2008).

  36. 36.

    Malovic, I. et al. The mannose receptor on murine liver sinusoidal endothelial cells is the main denatured collagen clearance receptor. Hepatology 45, 1454–1461 (2007).

  37. 37.

    Politz, O. et al. Stabilin-1 and -2 constitute a novel family of fasciclin-like hyaluronan receptor homologues. Biochem. J. 362, 155–164 (2002).

  38. 38.

    Bashirova, A. A. et al. A dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN)-related protein is highly expressed on human liver sinusoidal endothelial cells and promotes HIV-1 infection. J. Exp. Med. 193, 671–678 (2001).

  39. 39.

    Liu, W. et al. Characterization of a novel C-type lectin-like gene, LSECtin: demonstration of carbohydrate binding and expression in sinusoidal endothelial cells of liver and lymph node. J. Biol. Chem. 279, 18748–18758 (2004).

  40. 40.

    Lin, G. et al. Differential N-linked glycosylation of human immunodeficiency virus and Ebola virus envelope glycoproteins modulates interactions with DC-SIGN and DC-SIGNR. J. Virol. 77, 1337–1346 (2003).

  41. 41.

    Marzi, A. et al. DC-SIGN and DC-SIGNR interact with the glycoprotein of Marburg virus and the S protein of severe acute respiratory syndrome coronavirus. J. Virol. 78, 12090–12095 (2004).

  42. 42.

    Gramberg, T. et al. LSECtin interacts with filovirus glycoproteins and the spike protein of SARS coronavirus. Virology 340, 224–236 (2005).

  43. 43.

    Li, Y. et al. C-Type lectin LSECtin interacts with DC-SIGNR and is involved in hepatitis C virus binding. Mol. Cell Biochem. 327, 183–190 (2009).

  44. 44.

    Ganesan, L. P. et al. Rapid and efficient clearance of blood-borne virus by liver sinusoidal endothelium. PLoS Pathog. 7, e1002281 (2011).

  45. 45.

    Hellevik, T. et al. Transport of residual endocytosed products into terminal lysosomes occurs slowly in rat liver endothelial cells. Hepatology 28, 1378–1389 (1998).

  46. 46.

    Cormier, E. G. et al. CD81 is an entry coreceptor for hepatitis C virus. Proc. Natl Acad. Sci. USA 101, 7270–7274 (2004).

  47. 47.

    Breiner, K. M., Schaller, H. & Knolle, P. A. Endothelial cell-mediated uptake of a hepatitis B virus: a new concept of liver targeting of hepatotropic microorganisms. Hepatology 34, 803–808 (2001).

  48. 48.

    Rowe, I. A. et al. Paracrine signals from liver sinusoidal endothelium regulate hepatitis C virus replication. Hepatology 59, 375–384 (2014).

  49. 49.

    Giugliano, S. et al. Hepatitis C virus infection induces autocrine interferon signaling by human liver endothelial cells and release of exosomes, which inhibits viral replication. Gastroenterology 148, 392–402 e313 (2015).

  50. 50.

    Limmer, A. et al. Efficient presentation of exogenous antigen by liver endothelial cells to CD8+ T cells results in antigen-specific T cell tolerance. Nat. Med. 6, 1348–1354 (2000).

  51. 51.

    Burgdorf, S., Kautz, A., Bohnert, V., Knolle, P. A. & Kurts, C. Distinct pathways of antigen uptake and intracellular routing in CD4 and CD8 T cell activation. Science 316, 612–616 (2007).

  52. 52.

    Limmer, A. et al. Cross-presentation of oral antigens by liver sinusoidal endothelial cells leads to CD8 T cell tolerance. Eur. J. Immunol. 35, 2970–2981 (2005).

  53. 53.

    Diehl, L. et al. Tolerogenic maturation of liver sinusoidal endothelial cells promotes B7-homolog 1-dependent CD8+ T cell tolerance. Hepatology 47, 296–305 (2008).

  54. 54.

    Schurich, A. et al. Distinct kinetics and dynamics of cross-presentation in liver sinusoidal endothelial cells compared to dendritic cells. Hepatology 50, 909–919 (2009).

  55. 55.

    Hochst, B. et al. Liver sinusoidal endothelial cells contribute to CD8 T cell tolerance toward circulating carcinoembryonic antigen in mice. Hepatology 56, 1924–1933 (2012).

  56. 56.

    Schurich, A. et al. Dynamic regulation of CD8 T cell tolerance induction by liver sinusoidal endothelial cells. J. Immunol. 184, 4107–4114 (2010).

  57. 57.

    Bottcher, J. P. et al. IL-6 trans-signaling-dependent rapid development of cytotoxic CD8+ T cell function. Cell Rep. 8, 1318–1327 (2014).

  58. 58.

    Lohse, A. W. et al. Antigen-presenting function and B7 expression of murine sinusoidal endothelial cells and Kupffer cells. Gastroenterology 110, 1175–1181 (1996).

  59. 59.

    Knolle, P. A. et al. Induction of cytokine production in naive CD4(+) T cells by antigen- presenting murine liver sinusoidal endothelial cells but failure to induce differentiation toward Th1 cells. Gastroenterology 116, 1428–1440 (1999).

  60. 60.

    Carambia, A. et al. TGF-beta-dependent induction of CD4(+)CD25(+)Foxp3(+) Tregs by liver sinusoidal endothelial cells. J. Hepatol. 61, 594–599 (2014).

  61. 61.

    Carambia, A. et al. Inhibition of inflammatory CD4 T cell activity by murine liver sinusoidal endothelial cells. J. Hepatol. 58, 112–118 (2013).

  62. 62.

    Luth, S. et al. Ectopic expression of neural autoantigen in mouse liver suppresses experimental autoimmune neuroinflammation by inducing antigen-specific Tregs. J. Clin. Invest. 118, 3403–3410 (2008).

  63. 63.

    Carambia, A. et al. Nanoparticle-based autoantigen delivery to Treg-inducing liver sinusoidal endothelial cells enables control of autoimmunity in mice. J. Hepatol. 62, 1349–1356 (2015).

  64. 64.

    Tang, L. et al. Liver sinusoidal endothelial cell lectin, LSECtin, negatively regulates hepatic T cell immune response. Gastroenterology 137, 1498–1508.e5 (2009).

  65. 65.

    Lalor, P. F., Shields, P., Grant, A. & Adams, D. H. Recruitment of lymphocytes to the human liver. Immunol. Cell Biol. 80, 52–64 (2002).

  66. 66.

    Nourshargh, S. & Alon, R. Leukocyte migration into inflamed tissues. Immunity 41, 694–707 (2014).

  67. 67.

    McEver, R. P. Selectins: initiators of leucocyte adhesion and signalling at the vascular wall. Cardiovasc. Res. 107, 331–339 (2015).

  68. 68.

    Tanaka, Y. et al. T cell adhesion induced by proteoglycan-immobilized cytokine MIP-1 beta. Nature 361, 79–82 (1993).

  69. 69.

    Campbell, J. J. et al. Chemokines and the arrest of lymphocytes rolling under flow conditions. Science 279, 381–384 (1998).

  70. 70.

    Muller, W. A. Transendothelial migration: unifying principles from the endothelial perspective. Immunol. Rev. 273, 61–75 (2016).

  71. 71.

    Wong, J. et al. A minimal role for selectins in the recruitment of leukocytes into the inflamed liver microvasculature. J. Clin. Invest. 99, 2782–2790 (1997).

  72. 72.

    Adams, D. H., Hubscher, S. G., Fisher, N. C., Williams, A. & Robinson, M. Expression of E-selectin and E-selectin ligands in human liver inflammation. Hepatology 24, 533–538 (1996).

  73. 73.

    Campbell, J. J., Qin, S., Bacon, K. B., Mackay, C. R. & Butcher, E. C. Biology of chemokine and classical chemoattractant receptors: differential requirements for adhesion-triggering versus chemotactic responses in lymphoid cells. J. Cell Biol. 134, 255–266 (1996).

  74. 74.

    Lalor, P. F. & Adams, D. H. The liver: a model of organ-specific lymphocyte recruitment. Expert Rev. Mol. Med. 4, 1–16 (2002).

  75. 75.

    Lalor, P. F. et al. Association between receptor density, cellular activation, and transformation of adhesive behavior of flowing lymphocytes binding to VCAM-1. Eur. J. Immunol. 27, 1422–1426 (1997).

  76. 76.

    Habtezion, A., Nguyen, L. P., Hadeiba, H. & Butcher, E. C. Leukocyte trafficking to the small intestine and colon. Gastroenterology 150, 340–354 (2016).

  77. 77.

    Grant, A. J., Lalor, P. F., Hubscher, S. G., Briskin, M. & Adams, D. H. MAdCAM-1 expressed in chronic inflammatory liver disease supports mucosal lymphocyte adhesion to hepatic endothelium (MAdCAM-1 in chronic inflammatory liver disease). Hepatology 33, 1065–1072 (2001).

  78. 78.

    Grant, A. J., Lalor, P. F., Salmi, M., Jalkanen, S. & Adams, D. H. Homing of mucosal lymphocytes to the liver in the pathogenesis of hepatic complications of inflammatory bowel disease. Lancet 359, 150–157 (2002).

  79. 79.

    Barreiro, O. et al. Endothelial tetraspanin microdomains regulate leukocyte firm adhesion during extravasation. Blood 105, 2852–2861 (2005).

  80. 80.

    Barreiro, O. et al. Endothelial adhesion receptors are recruited to adherent leukocytes by inclusion in preformed tetraspanin nanoplatforms. J. Cell Biol. 183, 527–542 (2008).

  81. 81.

    Wadkin, J. C. R. et al. CD151 supports VCAM-1 mediated lymphocyte adhesion to liver endothelium and is upregulated in chronic liver disease and hepatocellular carcinoma. Am. J. Physiol. Gastrointest. Liver Physiol. 02016, G138–G149 (2017).

  82. 82.

    Salmi, M., Tohka, S., Berg, E. L., Butcher, E. C. & Jalkanen, S. Vascular adhesion protein 1 (VAP-1) mediates lymphocyte subtype-specific, selectin-independent recognition of vascular endothelium in human lymph nodes. J. Exp. Med. 186, 589–600 (1997).

  83. 83.

    Lalor, P. F. et al. Vascular adhesion protein-1 mediates adhesion and transmigration of lymphocytes on human hepatic endothelial cells. J. Immunol. 169, 983–992 (2002).

  84. 84.

    Bonder, C. S. et al. Rules of recruitment for Th1 and th2 lymphocytes in inflamed liver: a role for alpha-4 integrin and vascular adhesion protein-1. Immunity 23, 153–163 (2005).

  85. 85.

    Lalor, P. F. et al. Activation of vascular adhesion protein-1 on liver endothelium results in an NF-kappaB-dependent increase in lymphocyte adhesion. Hepatology 45, 465–474 (2007).

  86. 86.

    Weston, C. J. et al. Vascular adhesion protein-1 promotes liver inflammation and drives hepatic fibrosis. J. Clin. Invest. 125, 501–520 (2015).

  87. 87.

    Liaskou, E. et al. Regulation of mucosal addressin cell adhesion molecule 1 expression in human and mice by vascular adhesion protein 1 amine oxidase activity. Hepatology 53, 661–672 (2011).

  88. 88.

    Jung, M. Y., Park, S. Y. & Kim, I. S. Stabilin-2 is involved in lymphocyte adhesion to the hepatic sinusoidal endothelium via the interaction with alphaMbeta2 integrin. J. Leukoc. Biol. 82, 1156–1165 (2007).

  89. 89.

    Salmi, M., Koskinen, K., Henttinen, T., Elima, K. & Jalkanen, S. CLEVER-1 mediates lymphocyte transmigration through vascular and lymphatic endothelium. Blood 104, 3849–3857 (2004).

  90. 90.

    Shetty, S. et al. Common lymphatic endothelial and vascular endothelial receptor-1 mediates the transmigration of regulatory T cells across human hepatic sinusoidal endothelium. J. Immunol. 186, 4147–4155 (2011).

  91. 91.

    Phillipson, M. et al. Intraluminal crawling of neutrophils to emigration sites: a molecularly distinct process from adhesion in the recruitment cascade. J. Exp. Med. 203, 2569–2575 (2006).

  92. 92.

    Vestweber, D. How leukocytes cross the vascular endothelium. Nat. Rev. Immunol. 15, 692–704 (2015).

  93. 93.

    Wohlleber, D. et al. TNF-induced target cell killing by CTL activated through cross-presentation. Cell Rep. 2, 478–487 (2012).

  94. 94.

    Guidotti, L. G. et al. Immunosurveillance of the liver by intravascular effector CD8(+) T cells. Cell 161, 486–500 (2015).

  95. 95.

    Carman, C. V. et al. Transcellular diapedesis is initiated by invasive podosomes. Immunity 26, 784–797 (2007).

  96. 96.

    Patten, D. A. et al. Human liver sinusoidal endothelial cells promote intracellular crawling of lymphocytes during recruitment- a new step in migration. Hepatology 65, 294–309 (2016).

  97. 97.

    Moser, B. & Willimann, K. Chemokines: role in inflammation and immune surveillance. Ann Rheum. Dis. 63 (Suppl 2), ii84–ii89 (2004).

  98. 98.

    Rot, A. Chemokine patterning by glycosaminoglycans and interceptors. Front. Biosci. 15, 645–660 (2010).

  99. 99.

    Adams, D. H. et al. Hepatic expression of macrophage inflammatory protein-1 alpha and macrophage inflammatory protein-1 beta after liver transplantation. Transplantation 61, 817–825 (1996).

  100. 100.

    Afford, S. C. et al. Distinct patterns of chemokine expression are associated with leukocyte recruitment in alcoholic hepatitis and alcoholic cirrhosis. J. Pathol. 186, 82–89 (1998).

  101. 101.

    Shields, P. L. et al. Chemokine and chemokine receptor interactions provide a mechanism for selective T cell recruitment to specific liver compartments within hepatitis C-infected liver. J. Immunol. 163, 6236–6243 (1999).

  102. 102.

    Yoong, K. F. et al. Expression and function of CXC and CC chemokines in human malignant liver tumors: a role for human monokine induced by gamma-interferon in lymphocyte recruitment to hepatocellular carcinoma. Hepatology 30, 100–111 (1999).

  103. 103.

    Eksteen, B. et al. Hepatic endothelial CCL25 mediates the recruitment of CCR9+ gut-homing lymphocytes to the liver in primary sclerosing cholangitis. J. Exp. Med. 200, 1511–1517 (2004).

  104. 104.

    Goddard, S. et al. Differential expression of chemokines and chemokine receptors shapes the inflammatory response in rejecting human liver transplants. Transplantation 72, 1957–1967 (2001).

  105. 105.

    Curbishley, S. M., Eksteen, B., Gladue, R. P., Lalor, P. & Adams, D. H. CXCR3 activation promotes lymphocyte transendothelial migration across human hepatic endothelium under fluid flow. Am. J. Pathol. 167, 887–899 (2005).

  106. 106.

    Hokeness, K. L. et al. CXCR3-dependent recruitment of antigen-specific T lymphocytes to the liver during murine cytomegalovirus infection. J. Virol. 81, 1241–1250 (2007).

  107. 107.

    Heydtmann, M. et al. CXC chemokine ligand 16 promotes integrin-mediated adhesion of liver-infiltrating lymphocytes to cholangiocytes and hepatocytes within the inflamed human liver. J. Immunol. 174, 1055–1062 (2005).

  108. 108.

    Heydtmann, M. & Adams, D. H. Chemokines in the immunopathogenesis of hepatitis C infection. Hepatology 49, 676–688 (2009).

  109. 109.

    Geissmann, F. et al. Intravascular immune surveillance by CXCR6+ NKT cells patrolling liver sinusoids. PLoS Biol. 3, e113 (2005).

  110. 110.

    Schrage, A. et al. Enhanced T cell transmigration across the murine liver sinusoidal endothelium is mediated by transcytosis and surface presentation of chemokines. Hepatology 48, 1262–1272 (2008).

  111. 111.

    Neumann, K. et al. Chemokine transfer by liver sinusoidal endothelial cells contributes to the recruitment of CD4+ T cells into the murine liver. PLoS ONE 10, e0123867 (2015).

  112. 112.

    Eksteen, B., Afford, S. C., Wigmore, S. J., Holt, A. P. & Adams, D. H. Immune-mediated liver injury. Semin. Liver Dis. 27, 351–366 (2007).

  113. 113.

    Knolle, P. A. & Thimme, R. Hepatic immune regulation and its involvement in viral hepatitis infection. Gastroenterology 146, 1193–1207 (2014).

  114. 114.

    Makarova-Rusher, O. V., Medina-Echeverz, J., Duffy, A. G. & Greten, T. F. The yin and yang of evasion and immune activation in HCC. J. Hepatol. 62, 1420–1429 (2015).

  115. 115.

    Oo, Y. H. et al. CXCR3-dependent recruitment and CCR6-mediated positioning of Th-17 cells in the inflamed liver. J. Hepatol. 57, 1044–1051 (2012).

  116. 116.

    Oo, Y. H. et al. Distinct roles for CCR4 and CXCR3 in the recruitment and positioning of regulatory T cells in the inflamed human liver. J. Immunol. 184, 2886–2898 (2010).

  117. 117.

    Eksteen, B. et al. Epithelial inflammation is associated with CCL28 production and the recruitment of regulatory T cells expressing CCR10. J. Immunol. 177, 593–603 (2006).

  118. 118.

    Bertolino, P. et al. Early intrahepatic antigen-specific retention of naive CD8+ T cells is predominantly ICAM-1/LFA-1 dependent in mice. Hepatology 42, 1063–1071 (2005).

  119. 119.

    John, B. & Crispe, I. N. Passive and active mechanisms trap activated CD8+ T cells in the liver. J. Immunol. 172, 5222–5229 (2004).

  120. 120.

    Miles, A., Liaskou, E., Eksteen, B., Lalor, P. F. & Adams, D. H. CCL25 and CCL28 promote alpha4 beta7-integrin-dependent adhesion of lymphocytes to MAdCAM-1 under shear flow. Am. J. Physiol. Gastrointest. Liver Physiol. 294, G1257–G1267 (2008).

  121. 121.

    Edwards, S., Lalor, P. F., Nash, G. B., Rainger, G. E. & Adams, D. H. Lymphocyte traffic through sinusoidal endothelial cells is regulated by hepatocytes. Hepatology 41, 451–459 (2005).

  122. 122.

    Holt, A. P. et al. Liver myofibroblasts regulate infiltration and positioning of lymphocytes in human liver. Gastroenterology 136, 705–714 (2009).

  123. 123.

    Bruns, T. et al. CMV infection of human sinusoidal endothelium regulates hepatic T cell recruitment and activation. J. Hepatol. 63, 38–49 (2015).

  124. 124.

    Shetty, S. et al. Recruitment mechanisms of primary and malignant B cells to the human liver. Hepatology 56, 1521–1531 (2012).

  125. 125.

    Wang, J. et al. Visualizing the function and fate of neutrophils in sterile injury and repair. Science 358, 111–116 (2017).

  126. 126.

    McDonald, B. et al. Interaction of CD44 and hyaluronan is the dominant mechanism for neutrophil sequestration in inflamed liver sinusoids. J. Exp. Med. 205, 915–927 (2008).

  127. 127.

    Moles, A. et al. A TLR2/S100A9/CXCL-2 signaling network is necessary for neutrophil recruitment in acute and chronic liver injury in the mouse. J. Hepatol. 60, 782–791 (2014).

  128. 128.

    Wang, J. & Kubes, P. A. Reservoir of mature cavity macrophages that can rapidly invade visceral organs to affect tissue repair. Cell 165, 668–678 (2016).

  129. 129.

    Tacke, F. & Zimmermann, H. W. Macrophage heterogeneity in liver injury and fibrosis. J. Hepatol. 60, 1090–1096 (2014).

  130. 130.

    Dal-Secco, D. et al. A dynamic spectrum of monocytes arising from the in situ reprogramming of CCR2+ monocytes at a site of sterile injury. J. Exp. Med. 212, 447–456 (2015).

  131. 131.

    Aspinall, A. I. et al. CX(3)CR1 and vascular adhesion protein-1-dependent recruitment of CD16(+) monocytes across human liver sinusoidal endothelium. Hepatology 51, 2030–2039 (2010).

  132. 132.

    Liaskou, E. et al. Monocyte subsets in human liver disease show distinct phenotypic and functional characteristics. Hepatology 57, 385–398 (2013).

  133. 133.

    Bradfield, P. F. et al. JAM-C regulates unidirectional monocyte transendothelial migration in inflammation. Blood 110, 2545–2555 (2007).

  134. 134.

    Randolph, G. J., Sanchez-Schmitz, G., Liebman, R. M. & Schakel, K. The CD16(+) (FcgammaRIII(+)) subset of human monocytes preferentially becomes migratory dendritic cells in a model tissue setting. J. Exp. Med. 196, 517–527 (2002).

  135. 135.

    Zimmermann, H. W. et al. Bidirectional transendothelial migration of monocytes across hepatic sinusoidal endothelium shapes monocyte differentiation and regulates the balance between immunity and tolerance in liver. Hepatology 63, 233–246 (2016).

  136. 136.

    Zannetti, C. et al. Characterization of the inflammasome in human kupffer cells in response to synthetic agonists and pathogens. J. Immunol. 197, 356–367 (2016).

  137. 137.

    Tilg, H., Moschen, A. R. & Szabo, G. Interleukin-1 and inflammasomes in alcoholic liver disease/acute alcoholic hepatitis and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology 64, 955–965 (2016).

  138. 138.

    Knolle, P. A. et al. Role of sinusoidal endothelial cells of the liver in concanavalin A-induced hepatic injury in mice. Hepatology 24, 824–829 (1996).

  139. 139.

    Xu, B. et al. Capillarization of hepatic sinusoid by liver endothelial cell-reactive autoantibodies in patients with cirrhosis and chronic hepatitis. Am. J. Pathol. 163, 1275–1289 (2003).

  140. 140.

    Ford, A. J., Jain, G. & Rajagopalan, P. Designing a fibrotic microenvironment to investigate changes in human liver sinusoidal endothelial cell function. Acta Biomater. 24, 220–227 (2015).

  141. 141.

    Arii, S. & Imamura, M. Physiological role of sinusoidal endothelial cells and kupffer cells and their implication in the pathogenesis of liver injury. J. Hepatobiliary Pancreat Surg. 7, 40–48 (2000).

  142. 142.

    Tsuchida, T. & Friedman, S. L. Mechanisms of hepatic stellate cell activation. Nat. Rev. Gastroenterol. Hepatol. 14, 397–411 (2017).

  143. 143.

    Xie, G. et al. Role of differentiation of liver sinusoidal endothelial cells in progression and regression of hepatic fibrosis in rats. Gastroenterology 142, 918–927.e6 (2012).

  144. 144.

    Warren, A. et al. T lymphocytes interact with hepatocytes through fenestrations in murine liver sinusoidal endothelial cells. Hepatology 44, 1182–1190 (2006).

  145. 145.

    Rautou, P. E. et al. Abnormal plasma microparticles impair vasoconstrictor responses in patients with cirrhosis. Gastroenterology 143, 166–176.e6 (2012).

  146. 146.

    Yoong, K. F., McNab, G., Hubscher, S. G. & Adams, D. H. Vascular adhesion protein-1 and ICAM-1 support the adhesion of tumor-infiltrating lymphocytes to tumor endothelium in human hepatocellular carcinoma. J. Immunol. 160, 3978–3988 (1998).

  147. 147.

    McMahan, R. H., Porsche, C. E., Edwards, M. G. & Rosen, H. R. Free fatty acids differentially downregulate chemokines in liver sinusoidal endothelial cells: insights into non-alcoholic fatty liver disease. PLoS ONE 11, e0159217 (2016).

  148. 148.

    Connolly, M. K. et al. In hepatic fibrosis, liver sinusoidal endothelial cells acquire enhanced immunogenicity. J. Immunol. 185, 2200–2208 (2010).

  149. 149.

    Lalor, P. F. et al. Vascular adhesion protein-1 as a potential therapeutic target in liver disease. Ann. N Y Acad. Sci. 1110, 485–496 (2007).

  150. 150.

    de Graaf, K. L. et al. (2018) NI-0801, an anti-chemokine (C-X-C motif) ligand 10 antibody, in patients with primary biliary cholangitis and an incomplete response to ursodeoxycholic acid. Hepatology Communications 2, 492–503 (2018).

  151. 151.

    Lefebvre, E. et al. Pharmacokinetics, safety, and CCR2/CCR5 antagonist activity of cenicriviroc in participants with mild or moderate hepatic impairment. Clin. Transl Sci. 9, 139–148 (2016).

  152. 152.

    Hirschfield, G. M., Karlsen, T. H., Lindor, K. D. & Adams, D. H. Primary sclerosing cholangitis. Lancet 382, 1587–1599 (2013).

  153. 153.

    Alidori, S. et al. Deconvoluting hepatic processing of carbon nanotubes. Nat. Commun. 7, 12343 (2016).

  154. 154.

    Zuo, Y. et al. Novel roles of liver sinusoidal endothelial cell lectin in colon carcinoma cell adhesion, migration and in-vivo metastasis to the liver. Gut 62, 1169–1178 (2013).

  155. 155.

    Na, H. et al. Novel roles of DC-SIGNR in colon cancer cell adhesion, migration, invasion, and liver metastasis. J. Hematol. Oncol. 10, 28 (2017).

  156. 156.

    Couvelard, A., Scoazec, J. Y. & Feldmann, G. Expression of cell-cell and cell-matrix adhesion proteins by sinusoidal endothelial cells in the normal and cirrhotic human liver. Am. J. Pathol. 143, 738–752 (1993).

  157. 157.

    Miyao, M. et al. Pivotal role of liver sinusoidal endothelial cells in NAFLD/NASH progression. Lab. Invest. 95, 1130–1144 (2015).

  158. 158.

    Wang, B. Y., Ju, X. H., Fu, B. Y., Zhang, J. & Cao, Y. X. Effects of ethanol on liver sinusoidal endothelial cells-fenestrae of rats. Hepatobiliary Pancreat. Dis. Int. 4, 422–426 (2005).

  159. 159.

    Horn, T., Christoffersen, P. & Henriksen, J. H. Alcoholic liver injury: defenestration in noncirrhotic livers — a scanning electron microscopic study. Hepatology 7, 77–82 (1987).

  160. 160.

    Clark, S. A. et al. Defenestration of hepatic sinusoids as a cause of hyperlipoproteinaemia in alcoholics. Lancet 2, 1225–1227 (1988).

  161. 161.

    Steffan, A. M. et al. Mouse hepatitis virus type 3 infection provokes a decrease in the number of sinusoidal endothelial cell fenestrae both in vivo and in vitro. Hepatology 22, 395–401 (1995).

  162. 162.

    Ito, Y. et al. Age-related changes in the hepatic microcirculation in mice. Exp. Gerontol. 42, 789–797 (2007).

  163. 163.

    Koudelkova, P., Weber, G. & Mikulits, W. Liver sinusoidal endothelial cells escape senescence by loss of p19ARF. PLoS ONE 10, e0142134 (2015).

  164. 164.

    Onori, P. et al. Hepatic microvascular features in experimental cirrhosis: a structural and morphometrical study in CCl4-treated rats. J. Hepatol. 33, 555–563 (2000).

  165. 165.

    Fernandez, M. et al. Angiogenesis in liver disease. J. Hepatol. 50, 604–620 (2009).

  166. 166.

    Corpechot, C. et al. Hypoxia-induced VEGF and collagen I expressions are associated with angiogenesis and fibrogenesis in experimental cirrhosis. Hepatology 35, 1010–1021 (2002).

  167. 167.

    Rosmorduc, O. et al. Hepatocellular hypoxia-induced vascular endothelial growth factor expression and angiogenesis in experimental biliary cirrhosis. Am. J. Pathol. 155, 1065–1073 (1999).

  168. 168.

    Ding, B. S. et al. Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis. Nature 505, 97–102 (2014).

  169. 169.

    Peralta, C., Jimenez-Castro, M. B. & Gracia-Sancho, J. Hepatic ischemia and reperfusion injury: effects on the liver sinusoidal milieu. J. Hepatol. 59, 1094–1106 (2013).

  170. 170.

    Yazdani, H. O. et al. IL-33 exacerbates liver sterile inflammation by amplifying neutrophil extracellular trap formation. J. Hepatol. 68, 130–139 (2017).

  171. 171.

    Xie, G. et al. Hedgehog signalling regulates liver sinusoidal endothelial cell capillarisation. Gut 62, 299–309 (2013).

  172. 172.

    Rockey, D. C. & Chung, J. J. Reduced nitric oxide production by endothelial cells in cirrhotic rat liver: endothelial dysfunction in portal hypertension. Gastroenterology 114, 344–351 (1998).

  173. 173.

    Zhuang, P. Y. et al. Higher proliferation of peritumoral endothelial cells to IL-6/sIL-6R than tumoral endothelial cells in hepatocellular carcinoma. BMC Cancer 15, 830 (2015).

  174. 174.

    Geraud, C. et al. Endothelial transdifferentiation in hepatocellular carcinoma: loss of Stabilin-2 expression in peri-tumourous liver correlates with increased survival. Liver Int. 33, 1428–1440 (2013).

  175. 175.

    Yang, Y. et al. Discontinuation of anti-VEGF cancer therapy promotes metastasis through a liver revascularization mechanism. Nat. Commun. 7, 12680 (2016).

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Acknowledgements

The work of the authors is funded by the National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre at the University Hospitals Birmingham National Health Service (NHS) Foundation Trust and the University of Birmingham. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the UK Department of Health.

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Affiliations

  1. Centre for Liver Research and NIHR Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK

    • Shishir Shetty
    • , Patricia F. Lalor
    •  & David H. Adams
  2. Liver Unit, University Hospitals Birmingham NHS Trust, Birmingham, UK

    • Shishir Shetty
    • , Patricia F. Lalor
    •  & David H. Adams

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S.S. and P.F.L. researched data for the article, made substantial contributions to discussion of content and wrote the manuscript. D.H.A. reviewed and edited the manuscript before submission.

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The authors have no competing financial interests.

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Correspondence to David H. Adams.

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