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Cited by 554Liver physiology and pathologyImmune cells in cancerLiver Disease Diagnosis and Treatment

Hepatic macrophages in homeostasis and liver diseases: from pathogenesis to novel therapeutic strategies

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Ju, Cynthia, Tacke, Frank·2016·Cellular & Molecular Immunology
DOI 10.1038/cmi.2015.104PMC PMC4856798
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Abstract

Macrophages represent a major cell type of innate immunity and have emerged as a critical player and therapeutic target in many chronic inflammatory diseases. Hepatic macrophages consist of Kupffer cells, which are originated from the fetal yolk-sack, and infiltrated bone marrow-derived monocytes/macrophages. Hepatic macrophages play a central role in maintaining homeostasis of the liver and in the pathogenesis of liver injury, making them an attractive therapeutic target for liver diseases. However, the various populations of hepatic macrophages display different phenotypes and exert distinct functions. Thus, more research is required to better understand these cells to guide the development of macrophage-based therapeutic interventions. This review article will summarize the current knowledge on the origins and composition of hepatic macrophages, their functions in maintaining hepatic homeostasis, and their involvement in both promoting and resolving liver inflammation, injury, and fibrosis. Finally, the current strategies being developed to target hepatic macrophages for the treatment of liver diseases will be reviewed.

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References 138 · Cited by 554

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  1. Varol C, Mildner A, Jung S. Macrophages: development and tissue specialization. Annu Rev Immunol 2015; 33: 643–675. 25861979
  2. Tacke F, Zimmermann HW. Macrophage heterogeneity in liver injury and fibrosis. J Hepatol 2014; 60: 1090–1096. 24412603
  3. Lavin Y, Winter D, Blecher-Gonen R, David E, Keren-Shaul H, Merad M et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 2014; 159: 1312–1326. 25480296 PMC4437213
  4. Xue J, Schmidt SV, Sander J, Draffehn A, Krebs W, Quester I et al. Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity 2014; 40: 274–288. 24530056 PMC3991396
  5. Dal-Secco D, Wang J, Zeng Z, Kolaczkowska E, Wong CH, Petri B 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 2015; 212: 447–456. 25800956 PMC4387291
  6. Karlmark KR, Weiskirchen R, Zimmermann HW, Gassler N, Ginhoux F, Weber C et al. Hepatic recruitment of the inflammatory Gr1+ monocyte subset upon liver injury promotes hepatic fibrosis. Hepatology 2009; 50: 261–274. 19554540
  7. Heymann F, Peusquens J, Ludwig-Portugall I, Kohlhepp M, Ergen C, Niemietz P et al. Liver inflammation abrogates immunological tolerance induced by Kupffer cells. Hepatology 2015; 62: 279–291. 25810240
  8. Antoniades CG, Quaglia A, Taams LS, Mitry RR, Hussain M, Abeles R et al. Source and characterization of hepatic macrophages in acetaminophen-induced acute liver failure in humans. Hepatology 2012; 56: 735–746. 22334567
  9. Gonzalez-Dominguez E, Samaniego R, Flores-Sevilla JL, Campos-Campos SF, Gómez-Campos G, Salas A et al. CD163L1 and CLEC5A discriminate subsets of human resident and inflammatory macrophages in vivo. J Leukoc Biol 2015; 98: 453–466. 25877931
  10. Tacke F, Randolph GJ. Migratory fate and differentiation of blood monocyte subsets. Immunobiology 2006; 211: 609–618. 16920499
  11. Ingersoll MA, Spanbroek R, Lottaz C, Gautier EL, Frankenberger M, Hoffmann R et al. Comparison of gene expression profiles between human and mouse monocyte subsets. Blood 2010; 115: e10–e19. 19965649 PMC2810986
  12. Carlin LM, Auffray C, Geissmann F. Measuring intravascular migration of mouse Ly6C(low) monocytes in vivo using intravital microscopy. Curr Protoc Immunol 2013; Chapter 14:Unit 14.33.1–16. 23564685
  13. Carlin LM, Stamatiades EG, Auffray C, Hanna RN, Glover L, Vizcay-Barrena G et al. Nr4a1-dependent Ly6C(low) monocytes monitor endothelial cells and orchestrate their disposal. Cell 2013; 153: 362–375. 23582326 PMC3898614
  14. Collison JL, Carlin LM, Eichmann M, Geissmann F, Peakman M. Heterogeneity in the locomotory behavior of human monocyte subsets over human vascular endothelium in vitro. J Immunol 2015; 195: 1162–1170. 26085686
  15. Heymann F, Hammerich L, Storch D, Bartneck M, Huss S, Rüsseler V et al. Hepatic macrophage migration and differentiation critical for liver fibrosis is mediated by the chemokine receptor C-C motif chemokine receptor 8 in mice. Hepatology 2012; 55: 898–909. 22031018 PMC4533854
  16. 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: E3186–E3195. 23100531 PMC3503234
  17. You Q, Holt M, Yin H, Li G, Hu CJ, Ju C. Role of hepatic resident and infiltrating macrophages in liver repair after acute injury. Biochem Pharmacol 2013; 86: 836–843. 23876342 PMC3863645
  18. Liaskou E, Zimmermann HW, Li KK, Oo YH, Suresh S, Stamataki Z et al. Monocyte subsets in human liver disease show distinct phenotypic and functional characteristics. Hepatology 2013; 57: 385–398. 22911542 PMC4194426
  19. Zimmermann HW, Seidler S, Nattermann J, Nikolaus Gassler, Claus Hellerbrand, Alma Zernecke et al. Functional contribution of elevated circulating and hepatic non-classical CD14CD16 monocytes to inflammation and human liver fibrosis. PLoS One 2010; 5: e11049. 20548789 PMC2883575
  20. Jenne CN, Kubes P. Immune surveillance by the liver. Nat Immunol 2013; 14: 996–1006. 24048121
  21. 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: 226–229. 7790711
  22. You Q, Cheng L, Kedl RM, Ju C. Mechanism of T cell tolerance induction by murine hepatic Kupffer cells. Hepatology 2008; 48: 978–990. 18712788 PMC2600585
  23. Yan ML, Wang YD, Tian YF, Lai ZD, Yan LN. Inhibition of allogeneic T-cell response by Kupffer cells expressing indoleamine 2,3-dioxygenase. World J Gastroenterol 2010; 16: 636–640. 20128035 PMC2816279
  24. Elsegood CL, Chan CW, Degli-Esposti MA, Wikstrom ME, Domenichini A, Lazarus K et al. Kupffer cell-monocyte communication is essential for initiating murine liver progenitor cell-mediated liver regeneration. Hepatology 2015; 62: 1272–1284. 26173184
  25. Seki E, De MS, Osterreicher CH, Kluwe J, Osawa Y, Brenner DA et al. TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat Med 2007; 13: 1324–1332. 17952090
  26. Melgar-Lesmes P, Edelman ER. Monocyte-endothelial cell interactions in the regulation of vascular sprouting and liver regeneration in mouse. J Hepatol 2015; 63: 917–925. 26022689 PMC4575901
  27. Ehling J, Bartneck M, Wei X, Gremse F, Fech V, Möckel D et al. CCL2-dependent infiltrating macrophages promote angiogenesis in progressive liver fibrosis. Gut 2014; 63: 1960–1971. 24561613 PMC4216733
  28. Movita D, van de Garde MD, Biesta P, Kim Kreefft, Bart Haagmans, Elina Zuniga et al. Inflammatory monocytes recruited to the liver within 24 hours after virus-induced inflammation resemble Kupffer cells but are functionally distinct. J Virol 2015; 89: 4809–4817. 25673700 PMC4403491
  29. Zigmond E, Samia-Grinberg S, Pasmanik-Chor M, Brazowski E, Shibolet O, Halpern Z et al. Infiltrating monocyte-derived macrophages and resident kupffer cells display different ontogeny and functions in acute liver injury. J Immunol 2014; 193: 344–353. 24890723
  30. Holt MP, Cheng L, Ju C. Identification and characterization of infiltrating macrophages in acetaminophen-induced liver injury. J Leukoc Biol 2008; 84: 1410–1421. 18713872 PMC2614594
  31. Jenkins SJ, Ruckerl D, Cook PC, Jones LH, Finkelman FD, van Rooijen N et al. Local macrophage proliferation, rather than recruitment from the blood, is a signature of TH2 inflammation. Science 2011; 332: 1284–1288. 21566158 PMC3128495
  32. Laskin DL, Gardner CR, Price VF, Jollow DJ. Modulation of macrophage functioning abrogates the acute hepatotoxicity of acetaminophen. Hepatology 1995; 21: 1045–1050. 7705777
  33. Michael SL, Pumford NR, Mayeux PR, Niesman MR, Hinson JA. Pretreatment of mice with macrophage inactivators decreases acetaminophen hepatotoxicity and the formation of reactive oxygen and nitrogen species. Hepatology 1999; 30: 186–195. 10385655
  34. Bourdi M, Masubuchi Y, Reilly TP, Amouzadeh HR, Martin JL, George JW et al. Protection against acetaminophen-induced liver injury and lethality by interleukin 10: role of inducible nitric oxide synthase. Hepatology 2002; 35: 289–298. 11826401
  35. Ryan PM, Bourdi M, Korrapati MC, Proctor WR, Vasquez RA, Yee SB et al. Endogenous interleukin-4 regulates glutathione synthesis following acetaminophen-induced liver injury in mice. Chem Res Toxicol 2012; 25: 83–93. 22107450 PMC3259285
  36. Yee SB, Bourdi M, Masson MJ, Pohl LR. Hepatoprotective role of endogenous interleukin-13 in a murine model of acetaminophen-induced liver disease. Chem Res Toxicol 2007; 20: 734–744. 17439248
  37. Campion SN, Johnson R, Aleksunes LM, Goedken MJ, van Rooijen N, Scheffer GL et al. Hepatic Mrp4 induction following acetaminophen exposure is dependent on Kupffer cell function. Am J Physiol Gastrointest Liver Physiol 2008; 295: G294–G304. 18556419 PMC2519859
  38. Ju C, Reilly TP, Bourdi M, Radonovich MF, Brady JN, George JW et al. Protective role of Kupffer cells in acetaminophen-induced hepatic injury in mice. Chem Res Toxicol 2002; 15: 1504–1513. 12482232
  39. Stutchfield BM, Antoine DJ, Mackinnon AC, Gow DJ, Bain CC, Hawley CA et al. CSF1 Restores innate immunity after liver injury in mice and serum levels indicate outcomes of patients with acute liver failure. Gastroenterology 2015; 149: 1896–1909.e14 26344055 PMC4672154
  40. Morita A, Itoh Y, Toyama T, Fujii H, Nishioji K, Kirishima T et al. Activated Kupffer cells play an important role in intra-hepatic Th1-associated necro-inflammation in Concanavalin A-induced hepatic injury in mice. Hepatol Res 2003; 27: 143–150. 14563429
  41. Schumann J, Wolf D, Pahl A, Brune K, Papadopoulos T, van Rooijen N et al. Importance of Kupffer cells for T-cell-dependent liver injury in mice. Am J Pathol 2000; 157: 1671–1683. 11073826 PMC1885735
  42. Chen L, Xie XJ, Ye YF, Zhou L, Xie HY, Xie QF et al. Kupffer cells contribute to concanavalin A-induced hepatic injury through a Th1 but not Th17 type response-dependent pathway in mice. Hepatobiliary Pancreat Dis Int 2011; 10: 171–178. 21459724
  43. Erhardt A, Biburger M, Papadopoulos T, Tiegs G. IL-10, regulatory T cells, and Kupffer cells mediate tolerance in concanavalin A-induced liver injury in mice. Hepatology 2007; 45: 475–485. 17256743
  44. Erhardt A, Tiegs G. Tolerance induction in response to liver inflammation. Dig Dis 2010; 28: 86–92. 20460895
  45. Howard TK, Klintmalm GB, Cofer JB, Husberg BS, Goldstein RM, Gonwa TA. The influence of preservation injury on rejection in the hepatic transplant recipient. Transplantation 1990; 49: 103–107. 2300999
  46. Abu-Amara M, Yang SY, Tapuria N, Fuller B, Davidson B, Seifalian A. Liver ischemia/reperfusion injury: processes in inflammatory networks—a review. Liver Transpl 2010; 16: 1016–1032. 20818739
  47. Hardonk MJ, Dijkhuis FW, Hulstaert CE, Koudstaal J. Heterogeneity of rat liver and spleen macrophages in gadolinium chloride-induced elimination and repopulation. J Leukoc Biol 1992; 52: 296–302. 1522388
  48. Giakoustidis DE, Iliadis S, Tsantilas D, Papageorgiou G, Kontos N, Kostopoulou E et al. Blockade of Kupffer cells by gadolinium chloride reduces lipid peroxidation and protects liver from ischemia/reperfusion injury. Hepatogastroenterology 2003; 50: 1587–1592. 14571792
  49. Tomiyama K, Ikeda A, Ueki S, Nakao A, Stolz DB, Koike Y et al. Inhibition of Kupffer cell-mediated early proinflammatory response with carbon monoxide in transplant-induced hepatic ischemia/reperfusion injury in rats. Hepatology 2008; 48: 1608–1620. 18972563
  50. Ellett JD, Atkinson C, Evans ZP, Amani Z, Balish E, Schmidt MG et al. Murine Kupffer cells are protective in total hepatic ischemia/reperfusion injury with bowel congestion through IL-10. J Immunol 2010; 184: 5849–5858. 20400698 PMC2938026
  51. 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: 559–569. 20093775 PMC2810082
  52. Richards JA, Wigmore SJ, Devey LR. Heme oxygenase system in hepatic ischemia-reperfusion injury. World J Gastroenterol. 2010; 16: 6068–6078. 21182221 PMC3012573
  53. Zhai Y, Busuttil RW, Kupiec-Weglinski JW. Liver ischemia and reperfusion injury: new insights into mechanisms of innate-adaptive immune-mediated tissue inflammation. Am J Transplant 2011; 11: 1563–1569. 21668640 PMC3658307
  54. Helk E, Bernin H, Ernst T, Jacobs T, Heeren J, Tacke F et al. TNFalpha-mediated liver destruction by Kupffer cells and Ly6Chi monocytes during Entamoeba histolytica infection. PLoS Pathog 2013; 9: e1003096. 23300453 PMC3536671
  55. Morias Y, Abels C, Laoui D, Guilliams M, Schouppe E, Tacke F et al. Ly6C- Monocytes Regulate Parasite-Induced Liver Inflammation by Inducing the Differentiation of Pathogenic Ly6C+ Monocytes into Macrophages. PLoS Pathog 2015; 11: e1004873. 26020782 PMC4447383
  56. Karakucuk I, Dilly SA, Maxwell JD. Portal tract macrophages are increased in alcoholic liver disease. Histopathology 1989; 14: 245–253. 2785081
  57. Tapia-Abellan A, Martinez-Esparza M, Ruiz-Alcaraz AJ, Hernández-Caselles T, Martínez-Pascual C, Miras-López M et al. The peritoneal macrophage inflammatory profile in cirrhosis depends on the alcoholic or hepatitis C viral etiology and is related to ERK phosphorylation. BMC Immunol 2012; 13: 42. 22866973 PMC3496568
  58. Lee J, French B, Morgan T, French SW. The liver is populated by a broad spectrum of markers for macrophages. In alcoholic hepatitis the macrophages are M1 and M2. Exp Mol Pathol 2014; 96: 118–125. 24145004 PMC3944995
  59. Luna-Casado L, Diez-Ruiz A, Gutierrez-Gea F, Santos-Perez JL, Rico-Irles J, Wachter H et al. Increased peripheral mononuclear cells expression of adhesion molecules in alcoholic cirrhosis: its relation to immune activation. J Hepatol 1997; 27: 477–483. 9314124
  60. Afford SC, Fisher NC, Neil DA, Fear J, Brun P, Hubscher SG et al. Distinct patterns of chemokine expression are associated with leukocyte recruitment in alcoholic hepatitis and alcoholic cirrhosis. J Pathol 1998; 186: 82–89. 9875144
  61. Fisher NC, Neil DA, Williams A, Adams DH. Serum concentrations and peripheral secretion of the beta chemokines monocyte chemoattractant protein 1 and macrophage inflammatory protein 1alpha in alcoholic liver disease. Gut 1999; 45: 416–420. 10446112 PMC1727646
  62. McClain CJ, Barve S, Deaciuc I, Kugelmas M, Hill D. Cytokines in alcoholic liver disease. Semin Liver Dis 1999; 19: 205–219. 10422201
  63. Gobejishvili L, Barve S, Joshi-Barve S, Uriarte S, Song Z, McClain C. Chronic ethanol-mediated decrease in cAMP primes macrophages to enhanced LPS-inducible NF-kappaB activity and TNF expression: relevance to alcoholic liver disease. Am J Physiol Gastrointest Liver Physiol 2006; 291: G681–G688. 16751174
  64. Zhang Z, Bagby GJ, Stoltz D, Oliver P, Schwarzenberger PO, Kolls JK. Prolonged ethanol treatment enhances lipopolysaccharide/phorbol myristate acetate-induced tumor necrosis factor-alpha production in human monocytic cells. Alcohol Clin Exp Res 2001; 25: 444–449. 11290857
  65. Enomoto N, Ikejima K, Bradford BU, Rivera CA, Kono H, Goto M et al. Role of Kupffer cells and gut-derived endotoxins in alcoholic liver injury. J Gastroenterol Hepatol 2000; 15 Suppl: D20–D25. 10759216
  66. 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: 3476–3489. 22945633 PMC3461900
  67. Koop DR, Klopfenstein B, Iimuro Y, Thurman RG. Gadolinium chloride blocks alcohol-dependent liver toxicity in rats treated chronically with intragastric alcohol despite the induction of CYP2E1. Mol Pharmacol 1997; 51: 944–950. 9187260
  68. Mandrekar P, Ambade A, Lim A, Szabo G, Catalano D. An essential role for monocyte chemoattractant protein-1 in alcoholic liver injury: regulation of proinflammatory cytokines and hepatic steatosis in mice. Hepatology 2011; 54: 2185–2197. 21826694 PMC3342822
  69. Nagy LE. Recent insights into the role of the innate immune system in the development of alcoholic liver disease. Exp Biol Med (Maywood) 2003; 228: 882–890. 12968059
  70. 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: 657–665. 25030420 PMC4163632
  71. Naveau S, Chollet-Martin S, Dharancy S, Mathurin P, Jouet P, Piquet MA et al. A double-blind randomized controlled trial of infliximab associated with prednisolone in acute alcoholic hepatitis. Hepatology 2004; 39: 1390–1397. 15122768
  72. Ganem D, Prince AM. Hepatitis B virus infection—natural history and clinical consequences. N Engl J Med 2004; 350: 1118–1129. 15014185
  73. Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med 2001; 345: 41–52. 11439948
  74. Tu Z, Pierce RH, Kurtis J, Kuroki Y, Crispe IN, Orloff MS. Hepatitis C virus core protein subverts the antiviral activities of human Kupffer cells. Gastroenterology 2010; 138: 305–314. 19769973
  75. Chang S, Dolganiuc A, Szabo G. Toll-like receptors 1 and 6 are involved in TLR2-mediated macrophage activation by hepatitis C virus core and NS3 proteins. J Leukoc Biol 2007; 82: 479–487. 17595379
  76. Hosomura N, Kono H, Tsuchiya M, Ishii K, Ogiku M, Matsuda M et al. HCV-related proteins activate Kupffer cells isolated from human liver tissues. Dig Dis Sci 2011; 56: 1057–1064. 20848204
  77. Khakoo SI, Soni PN, Savage K, Brown D, Dhillon AP, Poulter LW et al. Lymphocyte and macrophage phenotypes in chronic hepatitis C infection. Correlation with disease activity. Am J Pathol 1997; 150: 963–970. 9060834 PMC1857904
  78. McGuinness PH, Painter D, Davies S, McCaughan GW. Increases in intrahepatic CD68 positive cells, MAC387 positive cells, and proinflammatory cytokines (particularly interleukin 18) in chronic hepatitis C infection. Gut 2000; 46: 260–269. 10644323 PMC1727823
  79. Burgio VL, Ballardini G, Artini M, Caratozzolo M, Bianchi FB, Levrero M. Expression of co-stimulatory molecules by Kupffer cells in chronic hepatitis of hepatitis C virus etiology. Hepatology 1998; 27: 1600–1606. 9620333
  80. 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: 1627–1636. 17916356 PMC2593079
  81. Shrivastava S, Mukherjee A, Ray R, Ray RB. Hepatitis C virus induces interleukin-1beta (IL-1beta)/IL-18 in circulatory and resident liver macrophages. J Virol 2013; 87: 12284–12290. 24006444 PMC3807883
  82. Boltjes A, Movita D, Boonstra A, Woltman AM. The role of Kupffer cells in hepatitis B and hepatitis C virus infections. J Hepatol 2014; 61: 660–671. 24798624
  83. Broering R, Wu J, Meng Z, Hilgard P, Lu M, Trippler M et al. Toll-like receptor-stimulated non-parenchymal liver cells can regulate hepatitis C virus replication. J Hepatol 2008; 48: 914–922. 18362039
  84. Zhu H, Liu C. Interleukin-1 inhibits hepatitis C virus subgenomic RNA replication by activation of extracellular regulated kinase pathway. J Virol 2003; 77: 5493–5498. 12692250 PMC153991
  85. Zhu H, Shang X, Terada N, Liu C. STAT3 induces anti-hepatitis C viral activity in liver cells. Biochem Biophys Res Commun 2004; 324: 518–528. 15474458
  86. Tordjmann T, Soulie A, Guettier C, Schmidt M, Berthou C, Beaugrand M et al. Perforin and granzyme B lytic protein expression during chronic viral and autoimmune hepatitis. Liver 1998; 18: 391–397. 9869393
  87. Tang TJ, Kwekkeboom J, Laman JD, Niesters HG, Zondervan PE, de Man RA et al. The role of intrahepatic immune effector cells in inflammatory liver injury and viral control during chronic hepatitis B infection. J Viral Hepat 2003; 10: 159–167. 12753333
  88. Kolios G, Valatas V, Kouroumalis E. Role of Kupffer cells in the pathogenesis of liver disease. World J Gastroenterol 2006; 12: 7413–7420. 17167827 PMC4087584
  89. Chang S, Dolganiuc A, Szabo G. Toll-like receptors 1 and 6 are involved in TLR2-mediated macrophage activation by hepatitis C virus core and NS3 proteins. J Leukoc Biol 2007; 82: 479–487. 17595379
  90. Li H, Zheng HW, Chen H, Xing ZZ, You H, Cong M et al. Hepatitis B virus particles preferably induce Kupffer cells to produce TGF-beta1 over pro-inflammatory cytokines. Dig Liver Dis 2012; 44: 328–333. 22177317
  91. Mengshol JA, Golden-Mason L, Arikawa T, Smith M, Niki T, McWilliams R et al. A crucial role for Kupffer cell-derived galectin-9 in regulation of T cell immunity in hepatitis C infection. PLoS One 2010; 5: e9504. 20209097 PMC2831996
  92. Sandler NG, Koh C, Roque A, Smith M, Niki T, McWilliams R et al. Host response to translocated microbial products predicts outcomes of patients with HBV or HCV infection. Gastroenterology 2011; 141: 1220–1230. 21726511 PMC3186837
  93. Nebbia G, Peppa D, Schurich A, Khanna P, Singh HD, Cheng Y et al. Upregulation of the Tim-3/galectin-9 pathway of T cell exhaustion in chronic hepatitis B virus infection. PLoS One 2012; 7: e47648. 23112829 PMC3480425
  94. Wallace K, Burt AD, Wright MC. Liver fibrosis. Biochem J 2008; 411: 1–18. 18333835
  95. Pradere JP, Kluwe J, De MS, Jiao JJ, Gwak GY, Dapito DH et al. Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice. Hepatology 2013; 58: 1461–1473. 23553591 PMC3848418
  96. Fallowfield JA, Mizuno M, Kendall TJ, Constandinou CM, Benyon RC, Duffield JS et al. Scar-associated macrophages are a major source of hepatic matrix metalloproteinase-13 and facilitate the resolution of murine hepatic fibrosis. J Immunol 2007; 178: 5288–5295. 17404313
  97. Pellicoro A, Aucott RL, Ramachandran P, Robson AJ, Fallowfield JA, Snowdon VK et al. Elastin accumulation is regulated at the level of degradation by macrophage metalloelastase (MMP-12) during experimental liver fibrosis. Hepatology 2012; 55: 1965–1975. 22223197
  98. 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. 15630444 PMC539199
  99. Baeck C, Wehr A, Karlmark KR, Heymann F, Vucur M, Gassler N et al. Pharmacological inhibition of the chemokine CCL2 (MCP-1) diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury. Gut 2012; 61: 416–426. 21813474
  100. Capece D, Fischietti M, Verzella D, Gaggiano A, Cicciarelli G, Tessitore A et al. The inflammatory microenvironment in hepatocellular carcinoma: a pivotal role for tumor-associated macrophages. Biomed Res Int 2013; 2013: 187204. 23533994 PMC3591180
  101. Naugler WE, Sakurai T, Kim S, Maeda S, Kim K, Elsharkawy AM et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 2007; 317: 121–124. 17615358
  102. Wu J, Li J, Salcedo R, Mivechi NF, Trinchieri G, Horuzsko A. The proinflammatory myeloid cell receptor TREM-1 controls Kupffer cell activation and development of hepatocellular carcinoma. Cancer Res 2012; 72: 3977–3986. 22719066 PMC3694446
  103. Wan S, Zhao E, Kryczek I, Mivechi NF, Trinchieri G, Horuzsko A. Tumor-associated macrophages produce interleukin 6 and signal via STAT3 to promote expansion of human hepatocellular carcinoma stem cells. Gastroenterology 2014; 147: 1393–1404. 25181692 PMC4253315
  104. Wu K, Kryczek I, Chen L, Zou W, Welling TH. Kupffer cell suppression of CD8+ T cells in human hepatocellular carcinoma is mediated by B7-H1/programmed death-1 interactions. Cancer Res 2009; 69: 8067–8075. 19826049 PMC4397483
  105. Kuang DM, Zhao Q, Peng C, Xu J, Zhang JP, Wu C et al. Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. J Exp Med 2009; 206: 1327–1337. 19451266 PMC2715058
  106. Ding T, Xu J, Wang F, Shi M, Zhang Y, Li S-P et al. High tumor-infiltrating macrophage density predicts poor prognosis in patients with primary hepatocellular carcinoma after resection. Hum Pathol 2009; 40: 381–389. 18992916
  107. Ikeda M, Ohkawa S, Okusaka T, Mitsunaga S, Kobayashi S, Morizane C et al. Japanese phase I study of GC33, a humanized antibody against glypican-3 for advanced hepatocellular carcinoma. Cancer Sci 2014; 105: 455–462. 24521523 PMC4317809
  108. Zhu AX, Gold PJ, El-Khoueiry AB, Abrams TA, Morikawa H, Ohishi N et al. First-in-man phase I study of GC33, a novel recombinant humanized antibody against glypican-3, in patients with advanced hepatocellular carcinoma. Clin Cancer Res 2013; 19: 920–928. 23362325
  109. Rogers TL, Wind N, Hughes R, Nutter F, Brown HK, Vasiliadou I et al. Macrophages as potential targets for zoledronic acid outside the skeleton-evidence from in vitro and in vivo models. Cell Oncol(Dordr.) 2013; 36: 505–514. 24177992 PMC13007476
  110. Coscia M, Quaglino E, Iezzi M, Curcio C, Pantaleoni F, Riganti C et al. Zoledronic acid repolarizes tumour-associated macrophages and inhibits mammary carcinogenesis by targeting the mevalonate pathway. J Cell Mol Med 2010; 14: 2803–2815. 19818098 PMC3822730
  111. Qin N, Yang F, Li A, Prifti E, Chen Y, Shao L et al. Alterations of the human gut microbiome in liver cirrhosis. Nature 2014; 513: 59–64. 25079328
  112. Mazagova M, Wang L, Anfora AT, Wissmueller M, Lesley SA, Miyamoto Y et al. Commensal microbiota is hepatoprotective and prevents liver fibrosis in mice. FASEB J 2015; 29: 1043–1055. 25466902 PMC4422368
  113. Preisser L, Miot C, Le Guillou-Guillemette H, Beaumont E, Foucher ED, Garo E et al. IL-34 and macrophage colony-stimulating factor are overexpressed in hepatitis C virus fibrosis and induce profibrotic macrophages that promote collagen synthesis by hepatic stellate cells. Hepatology 2014; 60: 1879–1890. 25066464
  114. Kedarisetty CK, Anand L, Bhardwaj A, Bhadoria AS, Kumar G, Vyas AK et al. Combination of granulocyte colony-stimulating factor and erythropoietin improves outcomes of patients with decompensated cirrhosis. Gastroenterology 2015; 148: 1362–1370. 25749502
  115. Bartneck M, Warzecha KT, Tacke F. Therapeutic targeting of liver inflammation and fibrosis by nanomedicine. Hepatobiliary Surg Nutr 2014; 3: 364–376. 25568860 PMC4273112
  116. Liu T, Li L, Fu C, Liu H, Chen D, Tang F. Pathological mechanisms of liver injury caused by continuous intraperitoneal injection of silica nanoparticles. Biomaterials 2012; 33: 2399–2407. 22182752
  117. Bartneck M, Ritz T, Keul HA, Wambach M, Bornemann J, Gbureck U et al. Peptide-functionalized gold nanorods increase liver injury in hepatitis. ACS Nano 2012; 6: 8767–8777. 22994679
  118. Bartneck M, Scheyda KM, Warzecha KT, Rizzo LY, Hittatiya K, Luedde T et al. Fluorescent cell-traceable dexamethasone-loaded liposomes for the treatment of inflammatory liver diseases. Biomaterials 2015; 37: 367–382. 25453965
  119. Bartneck M, Peters FM, Warzecha KT, Bienert M, van Bloois L, Trautwein C et al. Liposomal encapsulation of dexamethasone modulates cytotoxicity, inflammatory cytokine response, and migratory properties of primary human macrophages. Nanomedicine 2014; 10: 1209–1220. 24607939
  120. He C, Yin L, Tang C, Yin C. Multifunctional polymeric nanoparticles for oral delivery of TNF-alpha siRNA to macrophages. Biomaterials 2013; 34: 2843–2854. 23347838
  121. Hammerich L, Tacke F. Interleukins in chronic liver disease: lessons learned from experimental mouse models. Clin Exp Gastroenterol 2014; 7: 297–306. 25214799 PMC4158890
  122. Traber PG, Chou H, Zomer E, Hong F, Klyosov A, Fiel M-I et al. Regression of fibrosis and reversal of cirrhosis in rats by galectin inhibitors in thioacetamide-induced liver disease. PLoS One 2013; 8: e75361. 24130706 PMC3793988
  123. Traber PG, Zomer E. Therapy of experimental NASH and fibrosis with galectin inhibitors. PLoS One 2013; 8: e83481. 24367597 PMC3867460
  124. Iredale JP, Bataller R. Identifying molecular factors that contribute to resolution of liver fibrosis. Gastroenterology 2014; 146: 1160–1164. 24680971
  125. Tacke F, Trautwein C. Mechanisms of liver fibrosis resolution. J Hepatol 2015; 63: 1038–1039. 26232376
  126. King A, Barton D, Beard HA, Ni Than N, Moore J, Corbett C et al. REpeated AutoLogous Infusions of STem cells In Cirrhosis (REALISTIC): a multicentre, phase II, open-label, randomised controlled trial of repeated autologous infusions of granulocyte colony-stimulating factor (GCSF) mobilised CD133+ bone marrow stem cells in patients with cirrhosis. A study protocol for a randomised controlled trial. BMJ Open 2015; 5: e007700. PMC4368910 25795699

Authors
Ju, C., & Tacke, F.
Affiliations
  • University of Colorado Anschutz (US)
  • Universitätsklinikum Aachen (DE)
Corresponding author
  • Ju, Cynthia
  • Tacke, Frank
ORCID
Venue
Cellular & Molecular Immunology
Publisher
Springer Science and Business Media LLC
Published
2016-02-24
Volume
13
Issue
3
Pages
316-327
ISSN
  • 1672-7681 (ISSN-L)
  • 2042-0226
DOI
10.1038/cmi.2015.104
PMC
PMC4856798
OpenAlex
W2335972659
Cited by
554
References
138
Citations by year
2026: 37 · 2025: 59 · 2024: 43 · 2023: 49 · 2022: 57 · 2021: 56 · 2020: 66 · 2019: 62 · 2018: 63 · 2017: 54 · 2016: 7 · 2014: 1
FWCI
7.73
Type
journal article
Language
en
Open access
Licence
Locations
  • Cellular and Molecular Immunology (publishedVersion, cc-by-nc-sa)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • RWTH Publications (RWTH Aachen) (submittedVersion, other-oa)
Funders
  • Deutsche Forschungsgemeinschaft
  • National Institute on Alcohol Abuse and Alcoholism (U01AA021723, R21AA022387)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
Keywords
hepatic macrophages, Kupffer cells, liver homeostasis, liver disease, liver inflammation, liver fibrosis, liver injury, monocyte-derived macrophages, macrophage origin, innate immunity
MeSH terms
Animals, Homeostasis, Humans, Liver, Liver Diseases, Macrophages

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