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Cited by 952Liver physiology and pathologyImmune Response and InflammationAlcohol Consumption and Health Effects

Liver: An organ with predominant innate immunity

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Gao, Bin, Jeong, Won-Il, Tian, Zhigang·2008·Hepatology
DOI 10.1002/hep.22034
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Abstract

Blood circulating from the intestines to the liver is rich in bacterial products, environmental toxins, and food antigens. To effectively and quickly defend against potentially toxic agents without launching harmful immune responses, the liver relies on its strong innate immune system. This comprises enrichment of innate immune cells (such as macrophages, natural killer, natural killer T, and γδ T cells) and removal of waste molecules and immunologic elimination of microorganisms by liver endothelial cells and Kupffer cells. In addition, the liver also plays an important role in controlling systemic innate immunity through the biosynthesis of numerous soluble pathogen-recognition receptors and complement components. Conclusion: The liver is an organ with predominant innate immunity, playing an important role not only in host defenses against invading microorganisms and tumor transformation but also in liver injury and repair. Recent evidence suggests that innate immunity is also involved in the pathogenesis of liver fibrosis, providing novel therapeutic targets to treat such a liver disorder. (Hepatology 2007.)

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  • HSCs contribute directly to the liver's innate immunity through expression of a large repertoire of innate immune receptors.

    “They contribute directly to the liver’s robust and essential innate immunity through expression of a large repertoire of innate immune receptors (8, 27).”

    From Hepatic Stellate Cell-Immune Interactions in NASH (2022) · cites this paper as [27]

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References 56 · Cited by 952

Research works printed but not linked: 51

  1. Racanelli V, Rehermann B. The liver as an immunological organ. HEPA- TOLOGY 2006;43:S54-S62.
  2. Meylan E, Tschopp J, Karin M. Intracellular pattern recognition receptors in the host response. Nature 2006;442:39-44.
  3. Bouwman LH, Roos A, Terpstra OT, de Knijff P, van Hoek B, Verspaget HW, et al. Mannose binding lectin gene polymorphisms confer a major risk for severe infections after liver transplantation. Gastroenterology 2005;129:408-414.
  4. Morgan BP, Gasque P. Extrahepatic complement biosynthesis: where, when and why? Clin Exp Immunol 1997;107:1-7.
  5. Qin XB, Gao B. The complement system in liver diseases. Cell Mol Im- munol 2006;3:333-340.
  6. Hillebrandt S, Wasmuth HE, Weiskirchen R, Hellerbrand C, Keppeler H, Werth A, et al. Complement factor 5 is a quantitative trait gene that modifies liver fibrogenesis in mice and humans. Nat Genet 2005;37:835- 843.
  7. Pritchard MT, McMullen MR, Stavitsky AB, Cohen JI, Lin F, Medof ME, et al. Differential contributions of C3, C5, and decay-accelerating factor to ethanol-induced fatty liver in mice. Gastroenterology 2007;132:1117- 1126.
  8. Gustot T, Lemmers A, Moreno C, Nagy N, Quertinmont E, Nicaise C, et al. Differential liver sensitization to toll-like receptor pathways in mice with alcoholic fatty liver. HEPATOLOGY 2006;43:989-1000.
  9. Szabo G, Dolganiuc A, Mandrekar P. Pattern recognition receptors: a contemporary view on liver diseases. HEPATOLOGY 2006;44:287-298.
  10. Schwabe RF, Seki E, Brenner DA. Toll-like receptor signaling in the liver. Gastroenterology 2006;130:1886-1900.
  11. Sumpter R Jr, Loo YM, Foy E, Li K, Yoneyama M, Fujita T, et al. Regu- lating intracellular antiviral defense and permissiveness to hepatitis C virus RNA replication through a cellular RNA helicase, RIG-I. J Virol 2005;79: 2689-2699.
  12. Foy E, Li K, Sumpter R Jr, Loo YM, Johnson CL, Wang C, et al. Control of antiviral defenses through hepatitis C virus disruption of retinoic acid- HEPATOLOGY, Vol. 47, No. 2, 2008
  13. GAO, JEONG, AND TIAN 735 15273350, 2008, 2, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.22034, Wiley Online Library on [31/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License inducible gene-I signaling. Proc Natl Acad Sci U S A 2005;102:2986- 2991.
  14. Cheng G, Zhong J, Chisari FV. Inhibition of dsRNA-induced signaling in hepatitis C virus-infected cells by NS3 protease-dependent and -indepen- dent mechanisms. Proc Natl Acad Sci U S A 2006;103:8499-8504.
  15. Isogawa M, Robek MD, Furuichi Y, Chisari FV. Toll-like receptor signal- ing inhibits hepatitis B virus replication in vivo. J Virol 2005;79:7269- 7272.
  16. Thomas A, Laxton C, Rodman J, Myangar N, Horscroft N, Parkinson T. Investigating toll-like receptor agonists for potential to treat hepatitis C virus infection. Antimicrob Agents Chemother 2007;51:2969-2978.
  17. Doherty DG, O'Farrelly C. Innate and adaptive lymphoid cells in the human liver. Immunol Rev 2000;174:5-20.
  18. Wick MJ, Leithauser F, Reimann J. The hepatic immune system. Crit Rev Immunol 2002;22:47-103.
  19. Lanier LL. NK cell recognition. Annu Rev Immunol 2005;23:225-274.
  20. Vermijlen D, Luo D, Froelich CJ, Medema JP, Kummer JA, Willems E, et al. Hepatic natural killer cells exclusively kill splenic/blood natural killer- resistant tumor cells by the perforin/granzyme pathway. J Leukoc Biol 2002;72:668-676.
  21. Ishiyama K, Ohdan H, Ohira M, Mitsuta H, Arihiro K, Asahara T. Dif- ference in cytotoxicity against hepatocellular carcinoma between liver and periphery natural killer cells in humans. HEPATOLOGY 2006;43:362-372.
  22. Subleski JJ, Hall VL, Back TC, Ortaldo JR, Wiltrout RH. Enhanced antitumor response by divergent modulation of natural killer and natural killer T cells in the liver. Cancer Res 2006;66:11005-11012.
  23. Chen Y, Wei H, Gao B, Hu Z, Zheng S, Tian Z. Activation and function of hepatic NK cells in hepatitis B infection: an underinvestigated innate immune response. J Viral Hepat 2005;12:38-45.
  24. Khakoo SI, Thio CL, Martin MP, Brooks CR, Gao X, Astemborski J, et al. HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection. Science 2004;305:872-874.
  25. Sun R, Gao B. Negative regulation of liver regeneration by innate immu- nity (natural killer cells/interferon-gamma). Gastroenterology 2004;127: 1525-1539.
  26. 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;130:435-452.
  27. Melhem A, Muhanna N, Bishara A, Alvarez CE, Ilan Y, Bishara T, et al. Anti-fibrotic activity of NK cells in experimental liver injury through kill- ing of activated HSC. J Hepatol 2006;45:60-71.
  28. Kronenberg M. Toward an understanding of NKT cell biology: progress and paradoxes. Annu Rev Immunol 2005;23:877-900.
  29. Exley MA, Koziel MJ. To be or not to be NKT: NKT cells in the liver. HEPATOLOGY 2004;40:1033-1040.
  30. Dong ZJ, Wei HM, Sun R, Tian ZG. The roles of innate immune cells in liver injury and regeneration. Cell Mol Immunol 2007;4:241-252.
  31. Born WK, Reardon CL, O'Brien RL. The function of gammadelta T cells in innate immunity. Curr Opin Immunol 2006;18:31-38.
  32. Miyakawa R, Ichida T, Yamagiwa S, Miyaji C, Watanabe H, Sato Y, et al. Hepatic NK and NKT cells markedly decreased in two cases of drug- induced fulminant hepatic failure rescued by living donor liver transplan- tation. J Gastroenterol Hepatol 2005;20:1126-1130.
  33. Biburger M, Tiegs G. Alpha-galactosylceramide-induced liver injury in mice is mediated by TNF-alpha but independent of Kupffer cells. J Im- munol 2005;175:1540-1550.
  34. Crispe IN, Giannandrea M, Klein I, John B, Sampson B, Wuensch S. Cellular and molecular mechanisms of liver tolerance. Immunol Rev 2006; 213:101-118.
  35. Bertolino P, McCaughan GW, Bowen DG. Role of primary intrahepatic T-cell activation in the 'liver tolerance effect'. Immunol Cell Biol 2002;80: 84-92.
  36. John B, Crispe IN. TLR-4 regulates CD8ϩ T cell trapping in the liver. J Immunol 2005;175:1643-1650.
  37. Liu ZX, Han D, Gunawan B, Kaplowitz N. Neutrophil depletion protects against murine acetaminophen hepatotoxicity. HEPATOLOGY 2006;43: 1220-1230.
  38. Jaeschke H. Mechanisms of liver injury. II. Mechanisms of neutrophil- induced liver cell injury during hepatic ischemia-reperfusion and other acute inflammatory conditions. Am J Physiol Gastrointest Liver Physiol 2006;290:G1083-G1088.
  39. Selzner N, Selzner M, Odermatt B, Tian Y, Van Rooijen N, Clavien PA. ICAM-1 triggers liver regeneration through leukocyte recruitment and Kupffer cell-dependent release of TNF-alpha/IL-6 in mice. Gastroenterol- ogy 2003;124:692-700.
  40. Liu ZX, Govindarajan S, Kaplowitz N. Innate immune system plays a critical role in determining the progression and severity of acetaminophen hepatotoxicity. Gastroenterology 2004;127:1760-1774.
  41. Dong Z, Zhang J, Sun R, Wei H, Tian Z. Impairment of liver regeneration correlates with activated hepatic NKT cells in HBV transgenic mice. HEPA- TOLOGY 2007;45:1400-1412.
  42. Hines IN, Kremer M, Isayama F, Perry AW, Milton RJ, Black AL, et al. Impaired liver regeneration and increased oval cell numbers following T cell-mediated hepatitis. HEPATOLOGY 2007;46:229-241.
  43. Kato A, Gabay C, Okaya T, Lentsch AB. Specific role of interleukin-1 in hepatic neutrophil recruitment after ischemia/reperfusion. Am J Pathol 2002;161:1797-1803.
  44. Friedman SL, Rockey DC, Bissell DM. Hepatic fibrosis 2006: report of the third AASLD single topic conference. HEPATOLOGY 2007;45:242-249.
  45. Watanabe A, Hashmi A, Gomes D, Town T, Badou A, Flavell R, et al. Apoptotic hepatocyte DNA inhibits hepatic stellate cell chemotaxis via toll-like receptor 9. HEPATOLOGY 2007. doi:// Available at: http:// www3.interscience.wiley.com.
  46. Jeong WI, Park O, Radaeva S, Gao B. STAT1 inhibits liver fibrosis in mice by inhibiting stellate cell proliferation and stimulating NK cell cytotoxic- ity. HEPATOLOGY 2006;44:1441-1451.
  47. Duffield JS, Forbes SJ, Constandinou CM, Clay S, Partolina M, Vuthoori S, et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest 2005;115:56-65.
  48. Taimr P, Higuchi H, Kocova E, Rippe RA, Friedman S, Gores GJ. Acti- vated stellate cells express the TRAIL receptor-2/death receptor-5 and undergo TRAIL-mediated apoptosis. HEPATOLOGY 2003;37:87-95.
  49. Morishima C, Paschal DM, Wang CC, Yoshihara CS, Wood BL, Yeo AE, et al. Decreased NK cell frequency in chronic hepatitis C does not affect ex vivo cytolytic killing. HEPATOLOGY 2006;43:573-580.
  50. Takehara T, Tatsumi T, Suzuki T, Rucker EB III, Hennighausen L, Ji- nushi M, et al. Hepatocyte-specific disruption of Bcl-xL leads to continu- ous hepatocyte apoptosis and liver fibrotic responses. Gastroenterology 2004;127:1189-1197.
  51. Maher JJ. Interactions between hepatic stellate cells and the immune sys- tem. Semin Liver Dis 2001;21:417-426.

Authors
Gao, B., Jeong, W.-I., & Tian, Z.
Affiliations
  • National Institutes of Health (US)
  • University of Science and Technology of China (CN)
Corresponding author
Gao, Bin
ORCID
Venue
Hepatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2008-02
Volume
47
Issue
2
Pages
729-736
ISSN
0270-9139 (ISSN-L)
DOI
10.1002/hep.22034
OpenAlex
W2081536518
Cited by
952
References
56
Citations by year
2026: 20 · 2025: 43 · 2024: 69 · 2023: 75 · 2022: 57 · 2021: 67 · 2020: 58 · 2019: 67 · 2018: 67 · 2017: 57 · 2016: 63 · 2015: 36 · 2014: 46 · 2013: 53 · 2012: 51
FWCI
3.50
Type
journal article
Language
en
Open access
Licence
doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 2769 d)
Locations
  • Hepatology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
Keywords
Kupffer cells, hepatic macrophages, natural killer cells, NKT cells, γδ T cells, liver endothelial cells, pathogen recognition receptors, complement system, liver fibrosis
MeSH terms
Animals, Complement System Proteins, Complement Activation, Humans, Immunity, Innate, Killer Cells, Natural, Kupffer Cells, Liver, Liver Circulation, T-Lymphocytes, Hepatocytes

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