Skip to main content
Download PDF

The role of hepatic macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis

Laboratory Animal Research volume 34, pages 133–139 (2018)Cite this article

Abstract

Nonalcoholic steatohepatitis (NASH) is becoming common chronic liver disease because of the increasing global prevalence of obesity and consequently Nonalcoholic fatty liver disease (NAFLD). However, the mechanism for progression of NAFLD to NASH and then cirrhosis is not completely understood, yet. The triggering of these hepatic diseases is thought from hepatocyte injury caused by over-accumulated lipid toxicity. Injured hepatocytes release damage-associated molecular patterns (DAMPs), which can stimulate the Kupffer cells (KCs), liver-resident macrophages, to release pro-inflammatory cytokines and chemokines, and recruit monocyte-derived macrophages (MDMs). The increased activation of KCs and recruitment of MDMs accelerate the progression of NAFLD to NASH and cirrhosis. Therefore, characterization for activation of hepatic macrophages, both KCs and MDMs, is a baseline to figure out the progression of hepatic diseases. The purpose of this review is to discuss the current understanding of mechanisms of NAFLD and NASH, mainly focusing on characterization and function of hepatic macrophages and suggests the regulators of hepatic macrophages as the therapeutic target in hepatic diseases.

References

  1. Carr RM, Oranu A, Khungar V. Nonalcoholic Fatty Liver Disease: Pathophysiology and Management. Gastroenterol Clin North Am 2016; 45(45): 639–652.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Liu W, Baker RD, Bhatia T, Zhu L, Baker SS. Pathogenesis of nonalcoholic steatohepatitis. Cell Mol Life Sci 2016; 73(73): 1969–1987.

    Article  CAS  PubMed  Google Scholar 

  3. Caligiuri A, Gentilini A, Marra F. Molecular Pathogenesis of NASH. Int J Mol Sci 2016; 17(9).

    Google Scholar 

  4. Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology 1998; 114(114): 842–845.

    CAS  PubMed  Google Scholar 

  5. Lopez BG, Tsai MS, Baratta JL, Longmuir KJ, Robertson RT. Characterization of Kupffer cells in livers of developing mice. Comp Hepatol 2011; 10(10): 2.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Tsuchida T, Friedman SL. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol 2017; 14(14): 397–411.

    Article  CAS  PubMed  Google Scholar 

  7. Krenkel O, Tacke F. Liver macrophages in tissue homeostasis and disease. Nat Rev Immunol 2017; 17(17): 306–321.

    Article  CAS  PubMed  Google Scholar 

  8. 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(6): 100–109.

    PubMed  PubMed Central  Google Scholar 

  9. Ju C, Tacke F. Hepatic macrophages in homeostasis and liver diseases: from pathogenesis to novel therapeutic strategies. Cell Mol Immunol 2016; 13(13): 316–327.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Tacke F, Zimmermann HW. Macrophage heterogeneity in liver injury and fibrosis. J Hepatol 2014; 60(60): 1090–1096.

    Article  CAS  PubMed  Google Scholar 

  11. Devisscher L, Verhelst X, Colle I, Van Vlierberghe H, Geerts A. The role of macrophages in obesity-driven chronic liver disease. J Leukoc Biol 2016; 99(99): 693–698.

    Article  CAS  PubMed  Google Scholar 

  12. Scott CL, Zheng F, De Baetselier P, Martens L, Saeys Y, De Prijck S, Lippens S, Abels C, Schoonooghe S, Raes G, Devoogdt N, Lambrecht BN, Beschin A, Guilliams M. Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells. Nat Commun 2016; 7: 10321.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zhou D, Yang K, Chen L, Wang Y, Zhang W, Xu Z, Zuo J, Jiang H, Luan J. Macrophage polarization and function: new prospects for fibrotic disease. Immunol Cell Biol 2017; 95(95): 864–869.

    Article  CAS  PubMed  Google Scholar 

  14. Murray PJ, Wynn TA. Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol 2011; 11(11): 723–737.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Abdullah Z, Knolle PA. Liver macrophages in healthy and diseased liver. Pflugers Arch 2017; 469(3-4): 553–560.

    Article  CAS  PubMed  Google Scholar 

  16. Sun YY, Li XF, Meng XM, Huang C, Zhang L, Li J. Macrophage Phenotype in Liver Injury and Repair. Scand J Immunol 2017; 85(85): 166–174.

    Article  PubMed  Google Scholar 

  17. Duarte N, Coelho IC, Patarrão RS, Almeida JI, Penha-Goncalves C, Macedo MP. How Inflammation Impinges on NAFLD: A Role for Kupffer Cells. Biomed Res Int 2015; 2015: 984578.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Thomson AW, Knolle PA. Antigen-presenting cell function in the tolerogenic liver environment. Nat Rev Immunol 2010; 10(10): 753–766.

    Article  CAS  PubMed  Google Scholar 

  19. You Q, Cheng L, Kedl RM, Ju C. Mechanism of T cell tolerance induction by murine hepatic Kupffer cells. Hepatology 2008; 48(48): 978–990.

    Article  CAS  PubMed  Google Scholar 

  20. Lang PA, Recher M, Honke N, Scheu S, Borkens S, Gailus N, Krings C, Meryk A, Kulawik A, Cervantes-Barragan L, Van Rooijen N, Kalinke U, Ludewig B, Hengartner H, Harris N, Häussinger D, Ohashi PS, Zinkernagel RM, Lang KS. Tissue macrophages suppress viral replication and prevent severe immunopathology in an interferon-I-dependent manner in mice. Hepatology 2010; 52(52): 25–32.

    CAS  Google Scholar 

  21. Breous E, Somanathan S, Vandenberghe LH, Wilson JM. Hepatic regulatory T cells and Kupffer cells are crucial mediators of systemic T cell tolerance to antigens targeting murine liver. Hepatology 2009; 50(50): 612–621.

    Article  CAS  PubMed  Google Scholar 

  22. Bissell DM, Wang SS, Jarnagin WR, Roll FJ. Cell-specific expression of transforming growth factor-beta in rat liver. Evidence for autocrine regulation of hepatocyte proliferation. J Clin Invest 1995; 96(96): 447–455.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Knolle P, Schlaak J, Uhrig A, Kempf P, Meyer zum Büschenfelde KH, Gerken G. Human Kupffer cells secrete IL-10 in response to lipopolysaccharide (LPS) challenge. J Hepatol 1995; 22(22): 226–229.

    Article  CAS  PubMed  Google Scholar 

  24. Fujimoto M, Uemura M, Nakatani Y, Tsujita S, Hoppo K, Tamagawa T, Kitano H, Kikukawa M, Ann T, Ishii Y, Kojima H, Sakurai S, Tanaka R, Namisaki T, Noguchi R, Higashino T, Kikuchi E, Nishimura K, Takaya A, Fukui H. Plasma endotoxin and serum cytokine levels in patients with alcoholic hepatitis: relation to severity of liver disturbance. Alcohol Clin Exp Res 2000; 24(4 Suppl): 48s-54s.

    Google Scholar 

  25. Harte AL, da Silva NF, Creely SJ, McGee KC, Billyard T, Youssef-Elabd EM, Tripathi G, Ashour E, Abdalla MS, Sharada HM, Amin AI, Burt AD, Kumar S, Day CP, McTernan PG. Elevated endotoxin levels in non-alcoholic fatty liver disease. J Inflamm (Lond) 2010; 7: 15.

    Article  CAS  Google Scholar 

  26. Marí M, Caballero F, Colell A, Morales A, Caballeria J, Fernandez A, Enrich C, Fernandez-Checa JC, Garcia-Ruiz C. Mitochondrial free cholesterol loading sensitizes to TNF- and Fas- mediated steatohepatitis. Cell Metab 2006; 4(4): 185–198.

    Article  CAS  PubMed  Google Scholar 

  27. Adkins Y, Schie IW, Fedor D, Reddy A, Nguyen S, Zhou P, Kelley DS, Wu J. A novel mouse model of nonalcoholic steatohepatitis with significant insulin resistance. Lab Invest 2013; 93(93): 1313–1322.

    Article  CAS  PubMed  Google Scholar 

  28. Gomez Perdiguero E, Klapproth K, Schulz C, Busch K, Azzoni E, Crozet L, Garner H, Trouillet C, de Bruijn MF, Geissmann F, Rodewald HR. Tissue-resident macrophages originate from yolk- sac-derived erythro-myeloid progenitors. Nature 2015; 518(518): 547–551.

    Article  CAS  PubMed  Google Scholar 

  29. Antoniades CG, Quaglia A, Taams LS, Mitry RR, Hussain M, Abeles R, Possamai LA, Bruce M, McPhail M, Starling C, Wagner B, Barnardo A, Pomplun S, Auzinger G, Bernal W, Heaton N, Vergani D, Thursz MR, Wendon J. Source and characterization of hepatic macrophages in acetaminophen- induced acute liver failure in humans. Hepatology 2012; 56(56): 735–746.

    Article  CAS  PubMed  Google Scholar 

  30. Gonzalez-Dominguez É, Samaniego R, Flores-Sevilla JL, Campos-Campos SF, Gómez-Campos G, Salas A, Campos-Peña V, Corbí ÁL, Sánchez-Mateos P, Sánchez-Torres C. CD163L1 and CLEC5A discriminate subsets of human resident and inflammatory macrophages in vivo. J Leukoc Biol 2015; 98(98): 453–466.

    Article  CAS  PubMed  Google Scholar 

  31. Tacke F, Randolph GJ. Migratory fate and differentiation of blood monocyte subsets. Immunobiology 2006; 211(6-8): 609–618.

    CAS  PubMed  Google Scholar 

  32. Ingersoll MA, Spanbroek R, Lottaz C, Gautier EL, Frankenberger M, Hoffmann R, Lang R, Haniffa M, Collin M, Tacke F, Habenicht AJ, Ziegler-Heitbrock L, Randolph GJ. Comparison of gene expression profiles between human and mouse monocyte subsets. Blood 2010; 115(115): e10-9.

    Google Scholar 

  33. Karlmark KR, Weiskirchen R, Zimmermann HW, Gassier N, Ginhoux F, Weber C, Merad M, Luedde T, Trautwein C, Tacke F. Hepatic recruitment of the inflammatory Grl+monocyte subset upon liver injury promotes hepatic fibrosis. Hepatology 2009; 50(50): 261–274.

    Article  CAS  PubMed  Google Scholar 

  34. Liaskou E, Zimmermann HW, Li KK, Oo YH, Suresh S, Stamataki Z, Qureshi O, Lalor PF, Shaw J, Syn WK, Curbishley SM, Adams DH. Monocyte subsets in human liver disease show distinct phenotypic and functional characteristics. Hepatology 2013; 57(57): 385–398.

    CAS  PubMed  Google Scholar 

  35. Marra F, Tacke F. Roles for chemokines in liver disease. Gastroenterology 2014; 147(147): 577–594.

    Article  CAS  PubMed  Google Scholar 

  36. Wang M, You Q, Lor K, Chen F, Gao B, Ju C. Chronic alcohol ingestion modulates hepatic macrophage populations and functions in mice. J Leukoc Biol 2014; 96(96): 657–665.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Duffield JS, Forbes SJ, Constandinou CM, Clay S, Partolina M, Vuthoori S, Wu S, Lang R, Iredale JP. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest 2005; 115(115): 56–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hirsova P, Ibrahim SH, Gores GJ, Malhi H. Lipotoxic lethal and sublethal stress signaling in hepatocytes: relevance to NASH pathogenesis. J Lipid Res 2016; 57(57): 1758–1770.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ioannou GN, Subramanian S, Chait A, Haigh WG, Yeh MM, Farrell GC, Lee SP, Savard C. Cholesterol crystallization within hepatocyte lipid droplets and its role in murine NASH. J Lipid Res 2017; 58(58): 1067–1079.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bieghs V, Wouters K, van Gorp PJ, Gijbels MJ, de Winther MP, Binder CJ, Lütjohann D, Febbraio M, Moore KJ, van Bilsen M, Hofker MH, Shiri-Sverdlov R. Role of scavenger receptor A and CD36 in diet-induced nonalcoholic steatohepatitis in hyperlipidemic mice. Gastroenterology 2010; 138(138): 2477–2486.

    Article  CAS  PubMed  Google Scholar 

  41. Cai C, Zhu X, Li P, Li J, Gong J, Shen W, He K. NLRP3 Deletion Inhibits the Non-alcoholic Steatohepatitis Development and Inflammation in Kupffer Cells Induced by Palmitic Acid. Inflammation 2017; 40(40): 1875–1883.

    Article  CAS  PubMed  Google Scholar 

  42. Bieghs V, van Gorp PJ, Walenbergh SM, Gijbels MJ, Verheyen F, Buurman WA, Briles DE, Hofker MH, Binder CJ, Shiri-Sverdlov R. Specific immunization strategies against oxidized low-density lipoprotein: a novel way to reduce nonalcoholic steatohepatitis in mice. Hepatology 2012; 56(56): 894–903.

    Article  CAS  PubMed  Google Scholar 

  43. Hirsova P, Gores GJ. Death Receptor-Mediated Cell Death and Proinflammatory Signaling in Nonalcoholic Steatohepatitis. Cell Mol Gastroenterol Hepatol 2015; 1(1): 17–27.

    Article  PubMed  Google Scholar 

  44. Brenner C, Galluzzi L, Kepp O, Kroemer G. Decoding cell death signals in liver inflammation. J Hepatol 2013; 59(59): 583–594.

    Article  CAS  PubMed  Google Scholar 

  45. Luedde T, Kaplowitz N, Schwabe RF. Cell death and cell death responses in liver disease: mechanisms and clinical relevance. Gastroenterology 2014; 147(147): 765–783.

    Article  CAS  PubMed  Google Scholar 

  46. Camell C, Goldberg E, Dixit VD. Regulation of Nlrp3 inflammasome by dietary metabolites. Semin Immunol 2015; 27(27): 334–342.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. He K, Zhu X, Liu Y, Miao C, Wang T, Li P, Zhao L, Chen Y, Gong J, Cai C, Li J, Li S, Ruan XZ, Gong J. Inhibition of NLRP3 inflammasome by thioredoxin-interacting protein in mouse Kupffer cells as a regulatory mechanism for non-alcoholic fatty liver disease development. Oncotarget 2017; 8(8): 37657–37672.

    PubMed  PubMed Central  Google Scholar 

  48. Szabo G, Iracheta-Vellve A. Inflammasome activation in the liver: Focus on alcoholic and non-alcoholic steatohepatitis. Clin Res Hepatol Gastroenterol 2015; 39 Suppl 1: S18–23.

    Article  CAS  PubMed  Google Scholar 

  49. Kanda T, Matsuoka S, Yamazaki M, Shibata T, Nirei K, Takahashi H, Kaneko T, Fujisawa M, Higuchi T, Nakamura H, Matsumoto N, Yamagami H, Ogawa M, Imazu H, Kuroda K, Moriyama M. Apoptosis and non-alcoholic fatty liver diseases. World J Gastroenterol 2018; 24(24): 2661–2672.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Akazawa Y, Nakao K. Lipotoxicity pathways intersect in hepatocytes: Endoplasmic reticulum stress, c-Jun N-terminal kinase-1, and death receptors. Hepatol Res 2016; 46(46): 977–984.

    Article  CAS  PubMed  Google Scholar 

  51. Wree A, Mehal WZ, Feldstein AE. Targeting Cell Death and Sterile Inflammation Loop for the Treatment of Nonalcoholic Steatohepatitis. Semin Liver Dis 2016; 36(36): 27–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ashraf NU, Sheikh TA. Endoplasmic reticulum stress and Oxidative stress in the pathogenesis of Non-alcoholic fatty liver disease. Free Radic Res 2015; 49(49): 1405–1418.

    Article  CAS  PubMed  Google Scholar 

  53. Tacke F. Targeting hepatic macrophages to treat liver diseases. J Hepatol 2017; 66(66): 1300–1312.

    Article  CAS  PubMed  Google Scholar 

  54. Thomas P, Lazure DA, Moussa R, Bajenova O, Burke PA, Ganguly A, Forse RA. Identification of two novel LPS-binding proteins in Kupffer cells: implications in TNF-alpha production. J Endotoxin Res 2006; 12(12): 352–357.

    Article  CAS  PubMed  Google Scholar 

  55. Farrell GC, van Rooyen D, Gan L, Chitturi S. NASH is an Inflammatory Disorder: Pathogenic, Prognostic and Therapeutic Implications. Gut Liver 2012; 6(6): 149–171.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Rivera CA, Adegboyega P, van Rooijen N, Tagalicud A, Altaian 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(47): 571–579.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Xu Z, Zhang X, Lau J, Yu J. C-X-C motif chemokine 10 in non alcoholic steatohepatitis: role as a pro-inflammatory factor and clinical implication. Expert Rev Mol Med 2016; 18: el6.

  58. Stojsavljeviæ S, Gomerèiæ Palèiæ M, Viroviæ Jukiæ L, Smirèiæ Duvnjak L, Duvnjak M. Adipokines and proinflammatory cytokines, the key mediators in the pathogenesis of nonalcoholic fatty liver disease. World J Gastroenterol 2014; 20(20): 18070–18091.

    Article  CAS  Google Scholar 

  59. Nati M, Haddad D, Birkenfeld AL, Koch CA, Chavakis T, Chatzigeorgiou A. The role of immune cells in metabolism-related liver inflammation and development of non-alcoholic steatohepatitis (NASH). Re Endocr Metab Disord 2016; 17(17): 29–39.

    Article  CAS  Google Scholar 

  60. Nakamoto N, Kanai T. Role of toll-like receptors in immune activation and tolerance in the liver. Front Immunol 2014; 5: 221.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Gao B, Tsukamoto H. Inflammation in Alcoholic and Nonalcoholic Fatty Liver Disease: Friend or Foe? Gastroenterology 2016; 150(150): 1704–1709.

    PubMed  PubMed Central  Google Scholar 

  62. Heymann F, Tacke F. Immunology in the liver—from homeostasis to disease. Nat Rev Gastroenterol Hepatol 2016; 13(13): 88–110.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry, Lee Gil Ya Cancer and Diabetes Institute, GAIHST, Gachon University College of Medicine, Incheon, Korea

    Ji-Young Cha

  2. Gachon Medical Research Institute, Gil Medical Center, Incheon, Korea

    Ji-Young Cha

  3. Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, 50 Yonseiro, Seodaemun-gu, 03722, Seoul, Korea

    Da-Hyun Kim & Kyung-Hee Chun

  4. Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Korea

    Da-Hyun Kim & Kyung-Hee Chun

Authors
  1. Ji-Young Cha
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Da-Hyun Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kyung-Hee Chun
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kyung-Hee Chun.

Rights and permissions

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://doi.org/creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cha, JY., Kim, DH. & Chun, KH. The role of hepatic macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Lab Anim Res 34, 133–139 (2018). https://doi.org/10.5625/lar.2018.34.4.133

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.5625/lar.2018.34.4.133

Keywords

Laboratory Animal Research

ISSN: 2233-7660