Skip to main content
SpringerLink
Log in

The Uniqueness of Innate Immunity

  • Chapter
  • First Online:
Liver Immunology

  • 644 Accesses

Abstract

Innate immune response is the first line of host defense to infections and innate immunity also provides key initiation signals for adaptive immune responses. Importantly, the innate immune system is also alerted and activated by damaged self. The fundamental phases of the innate immune response, such as recognition, response, and resolution, are generally the same regardless of the initial trigger, allowing the host to return to normal homeostasis after responding to an infectious or sterile innate immune insult. However, in chronic liver diseases where persistent viral infection, metabolic danger signals or tissue injury is persistent for a prolonged period of time, the resolution phase of the immune response is never achieved, allowing persistent innate immune activation and inflammation. Such persistent, usually low-grade inflammation, contributes to chronic liver diseases and becomes the driver of progressive liver injury. Chronic inflammation in the liver leads to liver fibrosis and contributes to end-stage liver disease. The liver is rich in all cell types of the innate immune system, and innate immune cells are rapidly recruited to the liver from the bone marrow. In addition to classical cells of the innate immune system, hepatocytes and other liver parenchymal cells also express evolutionally preserved receptors and pathways that recognize danger at the molecular level. These include various pattern recognition receptors, Toll-like receptors (TLRs) and Nod-like receptors (NLRs). Activation of these innate immune signaling pathways results in production of interferons, chemokines, cytokines, and cellular activation. The uniqueness of innate immunity is discussed in this chapter.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 139.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
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. Robinson MW, Harmon C, O’Farrelly C. Liver immunology and its role in inflammation and homeostasis. Cell Mol Immunol. 2016;13(3):267–76.

    Article  CAS  Google Scholar 

  2. Szabo G, Dolganiuc A, Mandrekar P. Pattern recognition receptors: a contemporary view on liver diseases. Hepatology. 2006;44(2):287–98.

    Article  CAS  Google Scholar 

  3. Szabo G, Mandrekar P, Dolganiuc A. Innate immune response and hepatic inflammation. Semin Liver Dis. 2007;27(4):339–50.

    Article  CAS  Google Scholar 

  4. Lau AH, Thomson AW. Dendritic cells and immune regulation in the liver. Gut. 2003;52(2):307–14.

    Article  CAS  Google Scholar 

  5. Rahman AH, Aloman C. Dendritic cells and liver fibrosis. Biochim Biophys Acta. 2013;1832(7):998–1004.

    Article  CAS  Google Scholar 

  6. Sprangers S, de Vries TJ, Everts V. Monocyte heterogeneity: consequences for monocyte-derived immune cells. J Immunol Res. 2016;2016:1475435.

    Article  CAS  Google Scholar 

  7. Ramachandran P, Pellicoro A, Vernon MA, Boulter L, Aucott RL, Ali A, et al. Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis. Proc Natl Acad Sci U S A. 2012;109(46):E3186–95.

    Article  CAS  Google Scholar 

  8. Ginhoux F, Jung S. Monocytes and macrophages: developmental pathways and tissue homeostasis. Nat Rev Immunol. 2014;14(6):392–404.

    Article  CAS  Google Scholar 

  9. Guillot A, Tacke F. Liver macrophages: old dogmas and new insights. Hepatol Commun. 2019;3(6):730–43.

    Article  Google Scholar 

  10. Bartneck M, Fech V, Ehling J, Govaere O, Warzecha KT, Hittatiya K, et al. Histidine-rich glycoprotein promotes macrophage activation and inflammation in chronic liver disease. Hepatology. 2016;63(4):1310–24.

    CAS  Google Scholar 

  11. Wang J, Kubes P. A reservoir of mature cavity macrophages that can rapidly invade visceral organs to affect tissue repair. Cell. 2016;165(3):668–78.

    CAS  Google Scholar 

  12. Stark MA, Huo Y, Burcin TL, Morris MA, Olson TS, Ley K. Phagocytosis of apoptotic neutrophils regulates granulopoiesis via IL-23 and IL-17. Immunity. 2005;22(3):285–94.

    CAS  Google Scholar 

  13. Remmerie A, Scott CL. Macrophages and lipid metabolism. Cell Immunol. 2018;330:27–42.

    CAS  Google Scholar 

  14. Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology. 2010;52(5):1836–46.

    CAS  Google Scholar 

  15. Gomez Perdiguero E, Klapproth K, Schulz C, Busch K, Azzoni E, Crozet L, et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature. 2015;518(7540):547–51.

    Google Scholar 

  16. Davies LC, Jenkins SJ, Allen JE, Taylor PR. Tissue-resident macrophages. Nat Immunol. 2013;14(10):986–95.

    CAS  Google Scholar 

  17. David BA, Rezende RM, Antunes MM, Santos MM, Freitas Lopes MA, Diniz AB, et al. Combination of mass cytometry and imaging analysis reveals origin, location, and functional repopulation of liver myeloid cells in mice. Gastroenterology. 2016;151(6):1176–91.

    CAS  Google Scholar 

  18. Krenkel O, Tacke F. Liver macrophages in tissue homeostasis and disease. Nat Rev Immunol. 2017;17(5):306–21.

    CAS  Google Scholar 

  19. Wenfeng Z, Yakun W, Di M, Jianping G, Chuanxin W, Chun H. Kupffer cells: increasingly significant role in nonalcoholic fatty liver disease. Ann Hepatol. 2014;13(5):489–95.

    Google Scholar 

  20. Leroux A, Ferrere G, Godie V, Cailleux F, Renoud ML, Gaudin F, et al. Toxic lipids stored by Kupffer cells correlates with their pro-inflammatory phenotype at an early stage of steatohepatitis. J Hepatol. 2012;57(1):141–9.

    CAS  Google Scholar 

  21. Su L, Li N, Tang H, Lou Z, Chong X, Zhang C, et al. Kupffer cell-derived TNF-alpha promotes hepatocytes to produce CXCL1 and mobilize neutrophils in response to necrotic cells. Cell Death Dis. 2018;9(3):323.

    Google Scholar 

  22. Nagy LE. The role of innate immunity in alcoholic liver disease. Alcohol Res. 2015;37(2):237–50.

    Google Scholar 

  23. Alvarenga DM, Mattos MS, Araujo AM, Antunes MM, Menezes GB. Neutrophil biology within hepatic environment. Cell Tissue Res. 2018;371(3):589–98.

    CAS  Google Scholar 

  24. Papayannopoulos V. Neutrophil extracellular traps in immunity and disease. Nat Rev Immunol. 2018;18(2):134–47.

    CAS  Google Scholar 

  25. Eash KJ, Greenbaum AM, Gopalan PK, Link DC. CXCR2 and CXCR4 antagonistically regulate neutrophil trafficking from murine bone marrow. J Clin Invest. 2010;120(7):2423–31.

    CAS  Google Scholar 

  26. Bartneck M, Wang J. Therapeutic targeting of neutrophil granulocytes in inflammatory liver disease. Front Immunol. 2019;10:2257.

    CAS  Google Scholar 

  27. Tritto G, Bechlis Z, Stadlbauer V, Davies N, Frances R, Shah N, et al. Evidence of neutrophil functional defect despite inflammation in stable cirrhosis. J Hepatol. 2011;55(3):574–81.

    CAS  Google Scholar 

  28. Singh V, Sharma AK, Narasimhan RL, Bhalla A, Sharma N, Sharma R. Granulocyte colony-stimulating factor in severe alcoholic hepatitis: a randomized pilot study. Am J Gastroenterol. 2014;109(9):1417–23.

    CAS  Google Scholar 

  29. Zhou Z, Xu MJ, Cai Y, Wang W, Jiang JX, Varga ZV, et al. Neutrophil-hepatic stellate cell interactions promote fibrosis in experimental steatohepatitis. Cell Mol Gastroenterol Hepatol. 2018;5(3):399–413.

    Google Scholar 

  30. Szabo G, Dolganiuc A. Hepatitis C and innate immunity: recent advances. Clin Liver Dis. 2008;12(3):675–92, x.

    Article  Google Scholar 

  31. Soysa DR, Crispe IN. Subcapsular hepatic dendritic cells: hiding in plain sight. Gastroenterology. 2016;151(6):1065–7.

    Article  Google Scholar 

  32. Krueger PD, Kim TS, Sung SS, Braciale TJ, Hahn YS. Liver-resident CD103+ dendritic cells prime antiviral CD8+ T cells in situ. J Immunol. 2015;194(7):3213–22.

    Article  CAS  Google Scholar 

  33. Reizis B, Bunin A, Ghosh HS, Lewis KL, Sisirak V. Plasmacytoid dendritic cells: recent progress and open questions. Annu Rev Immunol. 2011;29:163–83.

    Article  CAS  Google Scholar 

  34. Nizzoli G, Krietsch J, Weick A, Steinfelder S, Facciotti F, Gruarin P, et al. Human CD1c+ dendritic cells secrete high levels of IL-12 and potently prime cytotoxic T-cell responses. Blood. 2013;122(6):932–42.

    Article  CAS  Google Scholar 

  35. Thomson AW, Knolle PA. Antigen-presenting cell function in the tolerogenic liver environment. Nat Rev Immunol. 2010;10(11):753–66.

    Article  CAS  Google Scholar 

  36. Crispe IN. Liver antigen-presenting cells. J Hepatol. 2011;54(2):357–65.

    Article  CAS  Google Scholar 

  37. Lu L, Woo J, Rao AS, Li Y, Watkins SC, Qian S, et al. Propagation of dendritic cell progenitors from normal mouse liver using granulocyte/macrophage colony-stimulating factor and their maturational development in the presence of type-1 collagen. J Exp Med. 1994;179(6):1823–34.

    Article  CAS  Google Scholar 

  38. Lukacs-Kornek V, Schuppan D. Dendritic cells in liver injury and fibrosis: shortcomings and promises. J Hepatol. 2013;59(5):1124–6.

    Article  CAS  Google Scholar 

  39. Manicassamy S, Pulendran B. Dendritic cell control of tolerogenic responses. Immunol Rev. 2011;241(1):206–27.

    Article  CAS  Google Scholar 

  40. Ibrahim J, Nguyen AH, Rehman A, Ochi A, Jamal M, Graffeo CS, et al. Dendritic cell populations with different concentrations of lipid regulate tolerance and immunity in mouse and human liver. Gastroenterology. 2012;143(4):1061–72.

    Article  CAS  Google Scholar 

  41. Gao B, Jeong WI, Tian Z. Liver: an organ with predominant innate immunity. Hepatology. 2008;47(2):729–36.

    Article  CAS  Google Scholar 

  42. Peng H, Jiang X, Chen Y, Sojka DK, Wei H, Gao X, et al. Liver-resident NK cells confer adaptive immunity in skin-contact inflammation. J Clin Invest. 2013;123(4):1444–56.

    Article  CAS  Google Scholar 

  43. Morvan MG, Lanier LL. NK cells and cancer: you can teach innate cells new tricks. (1474–1768 (Electronic)).

    Google Scholar 

  44. Radaeva S, Sun R, Jaruga B, Nguyen VT, Tian Z, Gao B. Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent manners. Gastroenterology. 2006;130(2):435–52.

    Article  CAS  Google Scholar 

  45. Oliviero B, Varchetta S, Paudice E, Michelone G, Zaramella M, Mavilio D, et al. Natural killer cell functional dichotomy in chronic hepatitis B and chronic hepatitis C virus infections. Gastroenterology. 2009;137(3):1151–60, 60.e1–7

    Article  CAS  Google Scholar 

  46. Dessouki O, Kamiya Y, Nagahama H, Tanaka M, Suzu S, Sasaki Y, et al. Chronic hepatitis C viral infection reduces NK cell frequency and suppresses cytokine secretion: reversion by anti-viral treatment. Biochem Biophys Res Commun. 2010;393(2):331–7.

    Article  CAS  Google Scholar 

  47. Ahlenstiel G, Titerence RH, Koh C, Edlich B, Feld JJ, Rotman Y, et al. Natural killer cells are polarized toward cytotoxicity in chronic hepatitis C in an interferon-alfa-dependent manner. Gastroenterology. 2010;138(1):325–35.e1–2.

    Article  CAS  Google Scholar 

  48. Liu P, Chen L, Zhang H. Natural killer cells in liver disease and hepatocellular carcinoma and the NK cell-based immunotherapy. J Immunol Res. 2018;2018:1206737.

    Google Scholar 

  49. Cai L, Zhang Z, Zhou L, Wang H, Fu J, Zhang S, et al. Functional impairment in circulating and intrahepatic NK cells and relative mechanism in hepatocellular carcinoma patients. Clin Immunol. 2008;129(3):428–37.

    Article  CAS  Google Scholar 

  50. Wu Y, Kuang DM, Pan WD, Wan YL, Lao XM, Wang D, et al. Monocyte/macrophage-elicited natural killer cell dysfunction in hepatocellular carcinoma is mediated by CD48/2B4 interactions. Hepatology. 2013;57(3):1107–16.

    Article  CAS  Google Scholar 

  51. Hoechst B, Voigtlaender T, Ormandy L, Gamrekelashvili J, Zhao F, Wedemeyer H, et al. Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 receptor. Hepatology. 2009;50(3):799–807.

    Article  CAS  Google Scholar 

  52. Li T, Yang Y, Hua X, Wang G, Liu W, Jia C, et al. Hepatocellular carcinoma-associated fibroblasts trigger NK cell dysfunction via PGE2 and IDO. Cancer Lett. 2012;318(2):154–61.

    Article  CAS  Google Scholar 

  53. Pillet AH, Theze J, Rose T. Interleukin (IL)-2 and IL-15 have different effects on human natural killer lymphocytes. Hum Immunol. 2011;72(11):1013–7.

    Article  CAS  Google Scholar 

  54. Gao B, Ahmad MF, Nagy LE, Tsukamoto H, Thorgersen EB, Barratt-Due A, et al. Inflammatory pathways in alcoholic steatohepatitisM2 Kupffer cells promote M1 Kupffer cell apoptosis: a protective mechanism against alcoholic and nonalcoholic fatty liver disease. (1600–0641 (Electronic)).

    Google Scholar 

  55. Gasteiger G, D’Osualdo A, Schubert DA, Weber A, Bruscia EM, Hartl D. Cellular innate immunity: an old game with new players. J Innate Immun. 2017;9(2):111–25.

    Article  CAS  Google Scholar 

  56. Liu J, Cao X. Advances in innate immune signaling: new activators and regulators. Natl Sci Rev. 2016;3(2):160–2.

    Article  CAS  Google Scholar 

  57. Jain A, Pasare C. Innate control of adaptive immunity: beyond the three-signal paradigm. J Immunol. 2017;198(10):3791–800.

    Article  CAS  Google Scholar 

  58. Iwasaki A, Medzhitov R. Control of adaptive immunity by the innate immune system. Nat Immunol. 2015;16(4):343–53.

    Article  CAS  Google Scholar 

  59. Tang D, Kang R, Coyne CB, Zeh HJ, Lotze MT. PAMPs and DAMPs: signal 0s that spur autophagy and immunity. Immunol Rev. 2012;249(1):158–75.

    Article  CAS  Google Scholar 

  60. Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol. 2007;81(1):1–5.

    Article  CAS  Google Scholar 

  61. Ioannou GN, Haigh WG, Thorning D, Savard C. Hepatic cholesterol crystals and crown-like structures distinguish NASH from simple steatosis. J Lipid Res. 2013;54(5):1326–34.

    Article  CAS  Google Scholar 

  62. Kawai T, Akira S. TLR signaling. Semin Immunol. 2007;19(1):24–32.

    Article  CAS  Google Scholar 

  63. Honda M, Kubes P. Neutrophils and neutrophil extracellular traps in the liver and gastrointestinal system. Nat Rev Gastroenterol Hepatol. 2018;15(4):206–21.

    Article  CAS  Google Scholar 

  64. Yousefi S, Mihalache C, Kozlowski E, Schmid I, Simon HU. Viable neutrophils release mitochondrial DNA to form neutrophil extracellular traps. Cell Death Differ. 2009;16(11):1438–44.

    Article  CAS  Google Scholar 

  65. Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W, et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature. 2010;464(7285):104–7.

    Article  CAS  Google Scholar 

  66. Bamboat ZM, Ocuin LM, Balachandran VP, Obaid H, Plitas G, DeMatteo RP. Conventional DCs reduce liver ischemia/reperfusion injury in mice via IL-10 secretion. J Clin Invest. 2010;120(2):559–69.

    Article  CAS  Google Scholar 

  67. Onoguchi K, Yoneyama M, Fujita T. Retinoic acid-inducible gene-I-like receptors. J Interf Cytokine Res. 2011;31(1):27–31.

    Article  CAS  Google Scholar 

  68. Loo YM, Gale M Jr. Immune signaling by RIG-I-like receptors. Immunity. 2011;34(5):680–92.

    Article  CAS  Google Scholar 

  69. Kang DC, Gopalkrishnan RV, Lin L, Randolph A, Valerie K, Pestka S, et al. Expression analysis and genomic characterization of human melanoma differentiation associated gene-5, mda-5: a novel type I interferon-responsive apoptosis-inducing gene. Oncogene. 2004;23(9):1789–800.

    Article  CAS  Google Scholar 

  70. Yoneyama M, Kikuchi M, Matsumoto K, Imaizumi T, Miyagishi M, Taira K, et al. Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity. J Immunol. 2005;175(5):2851–8.

    Article  CAS  Google Scholar 

  71. Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, Miyagishi M, et al. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol. 2004;5(7):730–7.

    Article  CAS  Google Scholar 

  72. Kayagaki N, Warming S, Lamkanfi M, Vande Walle L, Louie S, Dong J, et al. Non-canonical inflammasome activation targets caspase-11. Nature. 2011;479(7371):117–21.

    Article  CAS  Google Scholar 

  73. de Carvalho RVH, Andrade WA, Lima-Junior DS, Dilucca M, de Oliveira CV, Wang K, et al. Leishmania lipophosphoglycan triggers caspase-11 and the non-canonical activation of the NLRP3 inflammasome. Cell Rep. 2019;26(2):429–37.e5.

    Article  CAS  Google Scholar 

  74. Chen N, Ou Z, Zhang W, Zhu X, Li P, Gong J. Cathepsin B regulates non-canonical NLRP3 inflammasome pathway by modulating activation of caspase-11 in Kupffer cells. Cell Prolif. 2018;51(6):e12487.

    Article  CAS  Google Scholar 

  75. Kayagaki N, Stowe IB, Lee BL, O’Rourke K, Anderson K, Warming S, et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature. 2015;526(7575):666–71.

    Article  CAS  Google Scholar 

  76. Petrasek J, Bala S, Csak T, Lippai D, Kodys K, Menashy V, et al. IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice. J Clin Invest. 2012;122(10):3476–89.

    Article  CAS  Google Scholar 

  77. Han YP, Yan C, Zhou L, Qin L, Tsukamoto H. A matrix metalloproteinase-9 activation cascade by hepatic stellate cells in trans-differentiation in the three-dimensional extracellular matrix. J Biol Chem. 2007;282(17):12928–39.

    Article  CAS  Google Scholar 

  78. Christopher MJ, Liu F, Hilton MJ, Long F, Link DC. Suppression of CXCL12 production by bone marrow osteoblasts is a common and critical pathway for cytokine-induced mobilization. Blood. 2009;114(7):1331–9.

    Article  CAS  Google Scholar 

  79. Moles A, Murphy L, Wilson CL, Chakraborty JB, Fox C, Park EJ, 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. 2014;60(4):782–91.

    Article  CAS  Google Scholar 

  80. Zuchtriegel G, Uhl B, Puhr-Westerheide D, Pornbacher M, Lauber K, Krombach F, et al. Platelets guide leukocytes to their sites of extravasation. PLoS Biol. 2016;14(5):e1002459.

    Google Scholar 

  81. Ma HY, Xu J, Liu X, Zhu Y, Gao B, Karin M, et al. The role of IL-17 signaling in regulation of the liver-brain axis and intestinal permeability in Alcoholic Liver Disease. Curr Pathobiol Rep. 2016;4(1):27–35.

    CAS  Google Scholar 

  82. Affo S, Morales-Ibanez O, Rodrigo-Torres D, Altamirano J, Blaya D, Dapito DH, et al. CCL20 mediates lipopolysaccharide induced liver injury and is a potential driver of inflammation and fibrosis in alcoholic hepatitis. Gut. 2014;63(11):1782–92.

    CAS  Google Scholar 

  83. Raich-Regue D, Glancy M, Thomson AW. Regulatory dendritic cell therapy: from rodents to clinical application. Immunol Lett. 2014;161(2):216–21.

    CAS  Google Scholar 

  84. Serhan CN, Chiang N, Van Dyke TE. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol. 2008;8(5):349–61.

    CAS  Google Scholar 

  85. Yang W, Tao Y, Wu Y, Zhao X, Ye W, Zhao D, et al. Neutrophils promote the development of reparative macrophages mediated by ROS to orchestrate liver repair. Nat Commun. 2019;10(1):1076.

    Article  CAS  Google Scholar 

  86. Wilgus TA, Roy S, McDaniel JC. Neutrophils and wound repair: positive actions and negative reactions. Adv Wound Care (New Rochelle). 2013;2(7):379–88.

    Article  Google Scholar 

  87. Schauer C, Janko C, Munoz LE, Zhao Y, Kienhofer D, Frey B, et al. Aggregated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines. Nat Med. 2014;20(5):511–7.

    Article  CAS  Google Scholar 

  88. Thomas JA, Pope C, Wojtacha D, Robson AJ, Gordon-Walker TT, Hartland S, et al. Macrophage therapy for murine liver fibrosis recruits host effector cells improving fibrosis, regeneration, and function. Hepatology. 2011;53(6):2003–15.

    Article  CAS  Google Scholar 

  89. Tripathi A, Debelius J, Brenner DA, Karin M, Loomba R, Schnabl B, et al. The gut-liver axis and the intersection with the microbiome. Nat Rev Gastroenterol Hepatol. 2018;15(7):397–411.

    Article  CAS  Google Scholar 

  90. Albillos A, Gottardi A, Rescigno M. The gut-liver axis in liver disease: pathophysiological basis for therapy. J Hepatol. 2020;72(3):558–77.

    CAS  Google Scholar 

  91. Szabo G. Gut-liver axis in alcoholic liver disease. Gastroenterology. 2015;148(1):30–6.

    CAS  Google Scholar 

  92. Szabo G, Bala S. MicroRNAs in liver disease. Nat Rev Gastroenterol Hepatol. 2013;10(9):542–52.

    CAS  Google Scholar 

  93. Gyongyosi B, Cho Y, Lowe P, Calenda CD, Iracheta-Vellve A, Satishchandran A, et al. Alcohol-induced IL-17A production in Paneth cells amplifies endoplasmic reticulum stress, apoptosis, and inflammasome-IL-18 activation in the proximal small intestine in mice. Mucosal Immunol. 2019;12(4):930–44.

    CAS  Google Scholar 

  94. Lowe PP, Gyongyosi B, Satishchandran A, Iracheta-Vellve A, Ambade A, Kodys K, et al. Alcohol-related changes in the intestinal microbiome influence neutrophil infiltration, inflammation and steatosis in early alcoholic hepatitis in mice. PLoS One. 2017;12(3):e0174544.

    Google Scholar 

  95. Szabo G, Saha B. Alcohol’s effect on host defense. Alcohol Res. 2015;37(2):159–70.

    Google Scholar 

  96. van Rooijen N, OLC W, van de Dobbelsteen GPJM, Sanders A, editors. Macrophages in host defense mechanisms. Immunology of silicones. Berlin, Heidelberg: Springer Berlin Heidelberg; 1996.

    Google Scholar 

  97. Szabo G, Petrasek J. Gut-liver axis and sterile signals in the development of alcoholic liver disease. Alcohol Alcohol. 2017;52(4):414–24.

    CAS  Google Scholar 

  98. Bukong TN, Cho Y, Iracheta-Vellve A, Saha B, Lowe P, Adejumo A, et al. Abnormal neutrophil traps and impaired efferocytosis contribute to liver injury and sepsis severity after binge alcohol use. J Hepatol. 2018;69(5):1145–54.

    CAS  Google Scholar 

  99. Thurman RG. II. Alcoholic liver injury involves activation of Kupffer cells by endotoxin. Am J Phys. 1998;275(4):G605–11.

    CAS  Google Scholar 

  100. Rivera CA, Adegboyega P, van Rooijen N, Tagalicud A, Allman M, Wallace M. Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis. J Hepatol. 2007;47(4):571–9.

    CAS  Google Scholar 

  101. Ambade A, Lowe P, Kodys K, Catalano D, Gyongyosi B, Cho Y, et al. Pharmacological inhibition of CCR2/5 signaling prevents and reverses alcohol-induced liver damage, steatosis, and inflammation in mice. Hepatology. 2019;69(3):1105–21.

    CAS  Google Scholar 

  102. McClain CJ, Barve S, Deaciuc I, Kugelmas M, Hill D. Cytokines in alcoholic liver disease. Semin Liver Dis. 1999;19(2):205–19.

    CAS  Google Scholar 

  103. Hritz I, Mandrekar P, Velayudham A, Catalano D, Dolganiuc A, Kodys K, et al. The critical role of toll-like receptor (TLR) 4 in alcoholic liver disease is independent of the common TLR adapter MyD88. Hepatology. 2008;48(4):1224–31.

    CAS  Google Scholar 

  104. Petrasek J, Iracheta-Vellve A, Csak T, Satishchandran A, Kodys K, Kurt-Jones EA, et al. STING-IRF3 pathway links endoplasmic reticulum stress with hepatocyte apoptosis in early alcoholic liver disease. Proc Natl Acad Sci U S A. 2013;110(41):16544–9.

    CAS  Google Scholar 

  105. Szabo G, Petrasek J, Bala S. Innate immunity and alcoholic liver disease. Dig Dis. 2012;30 Suppl 1:55–60.

    Google Scholar 

  106. Szabo G, Csak T. Inflammasomes in liver diseases. J Hepatol. 2012;57(3):642–54.

    CAS  Google Scholar 

  107. Petrasek J, Csak T, Ganz M, Szabo G. Differences in innate immune signaling between alcoholic and non-alcoholic steatohepatitis. J Gastroenterol Hepatol. 2013;28 Suppl 1:93–8.

    Google Scholar 

  108. Iracheta-Vellve A, Petrasek J, Satishchandran A, Gyongyosi B, Saha B, Kodys K, et al. Inhibition of sterile danger signals, uric acid and ATP, prevents inflammasome activation and protects from alcoholic steatohepatitis in mice. J Hepatol. 2015;63(5):1147–55.

    CAS  Google Scholar 

  109. Petrasek J, Iracheta-Vellve A, Saha B, Satishchandran A, Kodys K, Fitzgerald KA, et al. Metabolic danger signals, uric acid and ATP, mediate inflammatory cross-talk between hepatocytes and immune cells in alcoholic liver disease. J Leukoc Biol. 2015;98(2):249–56.

    CAS  Google Scholar 

  110. Khanova E, Wu R, Wang W, Yan R, Chen Y, French SW, et al. Pyroptosis by caspase11/4-gasdermin-D pathway in alcoholic hepatitis in mice and patients. Hepatology. 2018;67(5):1737–53.

    Article  CAS  Google Scholar 

  111. Iracheta-Vellve A, Petrasek J, Gyogyosi B, Bala S, Csak T, Kodys K, et al. Interleukin-1 inhibition facilitates recovery from liver injury and promotes regeneration of hepatocytes in alcoholic hepatitis in mice. Liver Int. 2017;37(7):968–73.

    Article  CAS  Google Scholar 

  112. Cai J, Zhang XJ, Li H. The role of innate immune cells in nonalcoholic steatohepatitis. Hepatology. 2019;70(3):1026–37.

    Article  Google Scholar 

  113. Kazankov K, Jorgensen SMD, Thomsen KL, Moller HJ, Vilstrup H, George J, et al. The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Nat Rev Gastroenterol Hepatol. 2019;16(3):145–59.

    Article  CAS  Google Scholar 

  114. Miura K, Yang L, van Rooijen N, Ohnishi H, Seki E. Hepatic recruitment of macrophages promotes nonalcoholic steatohepatitis through CCR2. Am J Physiol Gastrointest Liver Physiol. 2012;302(11):G1310–21.

    Article  CAS  Google Scholar 

  115. Grunhut J, Wang W, Aykut B, Gakhal I, Torres-Hernandez A, Miller G. Macrophages in nonalcoholic steatohepatitis: friend or foe? Eur Med J Hepatol. 2018;6(1):100–9.

    Google Scholar 

  116. Csak T, Dolganiuc A, Kodys K, Nath B, Petrasek J, Bala S, et al. Mitochondrial antiviral signaling protein defect links impaired antiviral response and liver injury in steatohepatitis in mice. Hepatology. 2011;53(6):1917–31.

    Article  CAS  Google Scholar 

  117. Csak T, Ganz M, Pespisa J, Kodys K, Dolganiuc A, Szabo G. Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells. Hepatology. 2011;54(1):133–44.

    Article  CAS  Google Scholar 

  118. Csak T, Pillai A, Ganz M, Lippai D, Petrasek J, Park JK, et al. Both bone marrow-derived and non-bone marrow-derived cells contribute to AIM2 and NLRP3 inflammasome activation in a MyD88-dependent manner in dietary steatohepatitis. Liver Int. 2014;34(9):1402–13.

    Article  CAS  Google Scholar 

  119. Strazzabosco M, Fiorotto R, Cadamuro M, Spirli C, Mariotti V, Kaffe E, et al. Pathophysiologic implications of innate immunity and autoinflammation in the biliary epithelium. Biochim Biophys Acta Mol basis Dis. 2018;1864(4) Pt B:1374–9.

    Article  CAS  Google Scholar 

  120. Selmi C, Lleo A, Pasini S, Zuin M, Gershwin ME. Innate immunity and primary biliary cirrhosis. Curr Mol Med. 2009;9(1):45–51.

    CAS  Google Scholar 

  121. Mao TK, Lian ZX, Selmi C, Ichiki Y, Ashwood P, Ansari AA, et al. Altered monocyte responses to defined TLR ligands in patients with primary biliary cirrhosis. Hepatology. 2005;42(4):802–8.

    CAS  Google Scholar 

  122. Peng A, Ke P, Zhao R, Lu X, Zhang C, Huang X, et al. Elevated circulating CD14(low)CD16(+) monocyte subset in primary biliary cirrhosis correlates with liver injury and promotes Th1 polarization. Clin Exp Med. 2016;16(4):511–21.

    CAS  Google Scholar 

  123. Wu SJ, Yang YH, Tsuneyama K, Leung PS, Illarionov P, Gershwin ME, et al. Innate immunity and primary biliary cirrhosis: activated invariant natural killer T cells exacerbate murine autoimmune cholangitis and fibrosis. Hepatology. 2011;53(3):915–25.

    CAS  Google Scholar 

  124. Aron JH, Bowlus CL. The immunobiology of primary sclerosing cholangitis. Semin Immunopathol. 2009;31(3):383–97.

    Article  CAS  Google Scholar 

  125. Guicciardi ME, Trussoni CE, Krishnan A, Bronk SF, Lorenzo Pisarello MJ, O’Hara SP, et al. Macrophages contribute to the pathogenesis of sclerosing cholangitis in mice. J Hepatol. 2018;69(3):676–86.

    CAS  Google Scholar 

  126. Chen Y-Y, Arndtz K, Webb G, Corrigan M, Akiror S, Liaskou E, et al. Intrahepatic macrophage populations in the pathophysiology of primary sclerosing cholangitis. JHEP Rep. 2019;1(5):369–76.

    Article  Google Scholar 

  127. Szabo G, Dolganiuc A. The role of plasmacytoid dendritic cell-derived IFN alpha in antiviral immunity. Crit Rev Immunol. 2008;28(1):61–94.

    Article  CAS  Google Scholar 

  128. Dolganiuc A, Kodys K, Marshall C, Saha B, Zhang S, Bala S, et al. Type III interferons, IL-28 and IL-29, are increased in chronic HCV infection and induce myeloid dendritic cell-mediated FoxP3+ regulatory T cells. PLoS One. 2012;7(10):e44915.

    CAS  Google Scholar 

  129. Dolganiuc A, Norkina O, Kodys K, Catalano D, Bakis G, Marshall C, et al. Viral and host factors induce macrophage activation and loss of toll-like receptor tolerance in chronic HCV infection. Gastroenterology. 2007;133(5):1627–36.

    CAS  Google Scholar 

  130. Ringelhan M, Pfister D, O’Connor T, Pikarsky E, Heikenwalder M. The immunology of hepatocellular carcinoma. Nat Immunol. 2018;19(3):222–32.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Beth Israel Deaconess Medical Center, Harvard Medical School, Research and Academic Affairs, Boston, MA, USA

    Gyongyi Szabo & Jaclyn Mallard

Authors
  1. Gyongyi Szabo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jaclyn Mallard
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gyongyi Szabo .

Editor information

Editors and Affiliations

  1. Division of Rheumatology, Allergy and Clinical Immunology, The University of California School of Medicine, Davis, CA, USA

    M. Eric Gershwin

  2. Departments of Medicine and Surgery, Baylor College of Medicine, Houston, TX, USA

    John M. Vierling

  3. Department of Medicine, Teikyo University School of Medicine, Itabashi, Tokyo, Japan

    Atsushi Tanaka

  4. President, Hannover Medical School, Hannover, Germany

    Michael P. Manns

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Szabo, G., Mallard, J. (2020). The Uniqueness of Innate Immunity. In: Gershwin, M.E., M. Vierling, J., Tanaka, A., P. Manns, M. (eds) Liver Immunology . Springer, Cham. https://doi.org/10.1007/978-3-030-51709-0_3

Download citation

Publish with us

Policies and ethics

Search

Navigation