Targeting hepatic macrophages to treat liver diseases

Journal of Hepatology

Volumn 66, Issue 6, 2017, Pages 1300-1312

  Tacke, Frank ^a  

^a UNIVERSITY HOSPITAL RWTH AACHEN   (Germany)

Author keywords

Chemokine; Cholestasis; HBV; HCC; HCV; Kupffer cell; Liver fibrosis; Macrophage; Monocyte; NASH

Indexed keywords

CHEMOKINE RECEPTOR CCR2; MONOCYTE CHEMOTACTIC PROTEIN 1;

ALCOHOL LIVER DISEASE; CELL ACTIVATION; CELL DIFFERENTIATION; CELL INFILTRATION; CHOLESTASIS; HEPATIC STELLATE CELL; HOMEOSTASIS; HUMAN; KUPFFER CELL; LIVER CANCER; LIVER CELL; LIVER DISEASE; LIVER FIBROSIS; LIVER INJURY; MACROPHAGE; MACROPHAGE FUNCTION; METABOLIC DISORDER; MONOCYTE; NONALCOHOLIC FATTY LIVER; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; REVIEW; VIRUS HEPATITIS; ANIMAL; ANIMAL HEPATITIS; CLASSIFICATION; EXPERIMENTAL LIVER NEOPLASM; IMMUNOLOGY; LIVER CIRRHOSIS; TOXIC HEPATITIS;

ANIMALS; CHEMICAL AND DRUG INDUCED LIVER INJURY; CHOLESTASIS; HEPATITIS, VIRAL, ANIMAL; HOMEOSTASIS; HUMANS; KUPFFER CELLS; LIVER CIRRHOSIS; LIVER DISEASES; LIVER NEOPLASMS, EXPERIMENTAL; MACROPHAGES;

EID: 85017336945     PISSN: 01688278     EISSN: 16000641     Source Type: Journal    
DOI: 10.1016/j.jhep.2017.02.026     Document Type: Review

References (135)

1. Heymann, F., Tacke, F., Immunology in the liver–from homeostasis to disease. Nat Rev Gastroenterol Hepatol 13 (2016), 88–110.
2. Lopez, B.G., Tsai, M.S., Baratta, J.L., Longmuir, K.J., Robertson, R.T., Characterization of Kupffer cells in livers of developing mice. Comp Hepatol, 10, 2011, 2.
3. Tacke, F., Zimmermann, H.W., Macrophage heterogeneity in liver injury and fibrosis. J Hepatol 60 (2014), 1090–1096.
4. von Kupffer, K.W., Über Sternzellen der Leber. Arch Mikroskop Anat 12 (1876), 353–358.
5. 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 518 (2015), 547–551.
6. Mass, E., Ballesteros, I., Farlik, M., Halbritter, F., Gunther, P., Crozet, L., et al. Specification of tissue-resident macrophages during organogenesis. Science, 353, 2016.
7. Hoeffel, G., Chen, J., Lavin, Y., Low, D., Almeida, F.F., See, P., et al. C-Myb(+) erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages. Immunity 42 (2015), 665–678.
8. Varol, C., Mildner, A., Jung, S., Macrophages: development and tissue specialization. Ann Rev Immunol 33 (2015), 643–675.
9. Dal-Secco, D., Wang, J., Zeng, Z., Kolaczkowska, E., Wong, C.H., 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 212 (2015), 447–456.
10. Wang, J., Kubes, P., A reservoir of mature cavity macrophages that can rapidly invade visceral organs to affect tissue repair. Cell 165 (2016), 668–678.
11. 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 62 (2015), 279–291.
12. David, B.A., Rezende, R.M., Antunes, M.M., Santos, M.M., Freitas Lopes, M.A., Diniz, A.B., et al. Combination of mass cytometry and imaging analysis reveals origin, location, and functional repopulation of liver myeloid cells in mice. Gastroenterology 151 (2016), 1176–1191.
13. Helmy, K.Y., Katschke, K.J. Jr., Gorgani, N.N., Kljavin, N.M., Elliott, J.M., Diehl, L., et al. CRIg: a macrophage complement receptor required for phagocytosis of circulating pathogens. Cell 124 (2006), 915–927.
14. Zeng, Z., Surewaard, B.G., Wong, C.H., Geoghegan, J.A., Jenne, C.N., Kubes, P., CRIg functions as a macrophage pattern recognition receptor to directly bind and capture blood-borne gram-positive bacteria. Cell Host Microbe 20 (2016), 99–106.
15. Surewaard, B.G., Deniset, J.F., Zemp, F.J., Amrein, M., Otto, M., Conly, J., et al. Identification and treatment of the Staphylococcus aureus reservoir in vivo. J Exp Med 213 (2016), 1141–1151.
16. Strnad, P., Tacke, F., Koch, A., Trautwein, C., Liver – guardian, modifier and target of sepsis. Nat Rev Gastroenterol Hepatol 14 (2017), 55–66.
17. Ingersoll, M.A., Spanbroek, R., Lottaz, C., Gautier, E.L., Frankenberger, M., Hoffmann, R., et al. Comparison of gene expression profiles between human and mouse monocyte subsets. Blood 115 (2010), e10–e19.
18. Mossanen, J.C., Krenkel, O., Ergen, C., Govaere, O., Liepelt, A., Puengel, T., et al. Chemokine (C-C motif) receptor 2-positive monocytes aggravate the early phase of acetaminophen-induced acute liver injury. Hepatology 64 (2016), 1667–1682.
19. Auffray, C., Fogg, D., Garfa, M., Elain, G., Join-Lambert, O., Kayal, S., et al. Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science 317 (2007), 666–670.
20. Serbina, N.V., Pamer, E.G., Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nat Immunol 7 (2006), 311–317.
21. Swirski, F.K., Nahrendorf, M., Etzrodt, M., Wildgruber, M., Cortez-Retamozo, V., Panizzi, P., et al. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science 325 (2009), 612–616.
22. Karlmark, K.R., Weiskirchen, R., Zimmermann, H.W., Gassler, N., Ginhoux, F., Weber, C., et al. Hepatic recruitment of the inflammatory Gr1+ monocyte subset upon liver injury promotes hepatic fibrosis. Hepatology 50 (2009), 261–274.
23. Theurl, I., Hilgendorf, I., Nairz, M., Tymoszuk, P., Haschka, D., Asshoff, M., et al. On-demand erythrocyte disposal and iron recycling requires transient macrophages in the liver. Nat Med 22 (2016), 945–951.
24. Crispe, I.N., Liver antigen-presenting cells. J Hepatol 54 (2011), 357–365.
25. Murphy, T.L., Grajales-Reyes, G.E., Wu, X., Tussiwand, R., Briseno, C.G., Iwata, A., et al. Transcriptional control of dendritic cell development. Ann Rev Immunol 34 (2016), 93–119.
26. Scott, C.L., Zheng, F., De Baetselier, P., Martens, L., Saeys, Y., De Prijck, S., et al. Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells. Nat Commun, 7, 2016, 10321.
27. Beattie, L., Sawtell, A., Mann, J., Frame, T.C., Teal, B., Rivera de Labastida, F., et al. Bone marrow-derived and resident liver macrophages display unique transcriptomic signatures but similar biological functions. J Hepatol 65 (2016), 758–768.
28. Klein, I., Cornejo, J.C., Polakos, N.K., John, B., Wuensch, S.A., Topham, D.J., et al. Kupffer cell heterogeneity: functional properties of bone marrow derived and sessile hepatic macrophages. Blood 110 (2007), 4077–4085.
29. Ramachandran, P., Pellicoro, A., Vernon, M.A., Boulter, L., Aucott, R.L., 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 USA 109 (2012), E3186–E3195.
30. Liaskou, E., Zimmermann, H.W., Li, K.K., Oo, Y.H., Suresh, S., Stamataki, Z., et al. Monocyte subsets in human liver disease show distinct phenotypic and functional characteristics. Hepatology 57 (2013), 385–398.
31. Zimmermann, H.W., Seidler, S., Nattermann, J., Gassler, N., Hellerbrand, C., Zernecke, A., et al. Functional contribution of elevated circulating and hepatic non-classical CD14CD16 monocytes to inflammation and human liver fibrosis. PLoS One, 5, 2010, e11049.
32. Kelly, A., Fahey, R., Fletcher, J.M., Keogh, C., Carroll, A.G., Siddachari, R., et al. CD141(+) myeloid dendritic cells are enriched in healthy human liver. J Hepatol 60 (2014), 135–142.
33. Murray, P.J., Macrophage polarization. Ann Rev Physiol 79 (2017), 541–566.
34. Baeck, C., Wei, X., Bartneck, M., Fech, V., Heymann, F., Gassler, N., et al. Pharmacological inhibition of the chemokine C-C motif chemokine ligand 2 (monocyte chemoattractant protein 1) accelerates liver fibrosis regression by suppressing Ly-6C(+) macrophage infiltration in mice. Hepatology 59 (2014), 1060–1072.
35. 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 159 (2014), 1312–1326.
36. Xue, J., Schmidt, S.V., Sander, J., Draffehn, A., Krebs, W., Quester, I., et al. Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity 40 (2014), 274–288.
37. Bartneck, M., Fech, V., Ehling, J., Govaere, O., Warzecha, K.T., Hittatiya, K., et al. Histidine-rich glycoprotein promotes macrophage activation and inflammation in chronic liver disease. Hepatology 63 (2016), 1310–1324.
38. Murray, P.J., Allen, J.E., Biswas, S.K., Fisher, E.A., Gilroy, D.W., Goerdt, S., et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41 (2014), 14–20.
39. Ju, C., Tacke, F., Hepatic macrophages in homeostasis and liver diseases: from pathogenesis to novel therapeutic strategies. Cell Mol Immunol 13 (2016), 316–327.
40. Movita, D., van de Garde, M.D., Biesta, P., Kreefft, K., Haagmans, B., Zuniga, E., et al. Inflammatory monocytes recruited to the liver within 24 h after virus-induced inflammation resemble Kupffer cells but are functionally distinct. J Virol 89 (2015), 4809–4817.
41. Zhai, Y., Busuttil, R.W., Kupiec-Weglinski, J.W., Liver ischemia and reperfusion injury: new insights into mechanisms of innate-adaptive immune-mediated tissue inflammation. Am J Transplant 11 (2011), 1563–1569.
42. Bernal, W., Wendon, J., Acute liver failure. N Engl J Med 369 (2013), 2525–2534.
43. Krenkel, O., Mossanen, J.C., Tacke, F., Immune mechanisms in acetaminophen-induced acute liver failure. Hepatobiliary Surg Nutr 3 (2014), 331–343.
44. Huebener, P., Pradere, J.P., Hernandez, C., Gwak, G.Y., Caviglia, J.M., Mu, X., et al. The HMGB1/RAGE axis triggers neutrophil-mediated injury amplification following necrosis. J Clin Invest 125 (2015), 539–550.
45. 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 193 (2014), 344–353.
46. Holt, M.P., Cheng, L., Ju, C., Identification and characterization of infiltrating macrophages in acetaminophen-induced liver injury. J Leukoc Biol 84 (2008), 1410–1421.
47. Antoniades, C.G., Quaglia, A., Taams, L.S., Mitry, R.R., Hussain, M., Abeles, R., et al. Source and characterization of hepatic macrophages in acetaminophen-induced acute liver failure in humans. Hepatology 56 (2012), 735–746.
48. Moore, J.K., MacKinnon, A.C., Man, T.Y., Manning, J.R., Forbes, S.J., Simpson, K.J., Patients with the worst outcomes after paracetamol (acetaminophen)-induced liver failure have an early monocytopenia. Aliment Pharmacol Ther 45 (2017), 443–454.
49. Bourdi, M., Masubuchi, Y., Reilly, T.P., Amouzadeh, H.R., Martin, J.L., George, J.W., et al. Protection against acetaminophen-induced liver injury and lethality by interleukin 10: role of inducible nitric oxide synthase. Hepatology 35 (2002), 289–298.
50. Ju, C., Reilly, T.P., Bourdi, M., Radonovich, M.F., Brady, J.N., George, J.W., et al. Protective role of Kupffer cells in acetaminophen-induced hepatic injury in mice. Chem Res Toxicol 15 (2002), 1504–1513.
51. You, Q., Holt, M., Yin, H., Li, G., Hu, C.J., Ju, C., Role of hepatic resident and infiltrating macrophages in liver repair after acute injury. Biochem Pharmacol 86 (2013), 836–843.
52. Stutchfield, B.M., Antoine, D.J., Mackinnon, A.C., Gow, D.J., Bain, C.C., Hawley, C.A., et al. CSF1 restores innate immunity after liver injury in mice and serum levels indicate outcomes of patients with acute liver failure. Gastroenterology 149 (2015), 1896–1909.
53. Antoniades, C.G., Khamri, W., Abeles, R.D., Taams, L.S., Triantafyllou, E., Possamai, L.A., et al. Secretory leukocyte protease inhibitor: a pivotal mediator of anti-inflammatory responses in acetaminophen-induced acute liver failure. Hepatology 59 (2014), 1564–1576.
54. Bird, T.G., Lu, W.Y., Boulter, L., Gordon-Keylock, S., Ridgway, R.A., Williams, M.J., et al. Bone marrow injection stimulates hepatic ductular reactions in the absence of injury via macrophage-mediated TWEAK signaling. Proc Natl Acad Sci USA 110 (2013), 6542–6547.
55. Boulter, L., Govaere, O., Bird, T.G., Radulescu, S., Ramachandran, P., Pellicoro, A., et al. Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Nat Med 18 (2012), 572–579.
56. van de Garde, M.D., Movita, D., van der Heide, M., Herschke, F., De Jonghe, S., Gama, L., et al. Liver monocytes and kupffer cells remain transcriptionally distinct during chronic viral infection. PLoS One, 11, 2016, e0166094.
57. Boltjes, A., Movita, D., Boonstra, A., Woltman, A.M., The role of Kupffer cells in hepatitis B and hepatitis C virus infections. J Hepatol 61 (2014), 660–671.
58. Boltjes, A., van Montfoort, N., Biesta, P.J., Op den Brouw, M.L., Kwekkeboom, J., van der Laan, L.J., et al. Kupffer cells interact with hepatitis B surface antigen in vivo and in vitro, leading to proinflammatory cytokine production and natural killer cell function. J Infect Dis 211 (2015), 1268–1278.
59. Tu, Z., Bozorgzadeh, A., Pierce, R.H., Kurtis, J., Crispe, I.N., Orloff, M.S., TLR-dependent cross talk between human Kupffer cells and NK cells. J Exp Med 205 (2008), 233–244.
60. Shrivastava, S., Mukherjee, A., Ray, R., Ray, R.B., Hepatitis C virus induces interleukin-1beta (IL-1beta)/IL-18 in circulatory and resident liver macrophages. J Virol 87 (2013), 12284–12290.
61. 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 82 (2007), 479–487.
62. 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 56 (2011), 1057–1064.
63. Tu, Z., Pierce, R.H., Kurtis, J., Kuroki, Y., Crispe, I.N., Orloff, M.S., Hepatitis C virus core protein subverts the antiviral activities of human Kupffer cells. Gastroenterology 138 (2010), 305–314.
64. McGuinness, P.H., Painter, D., Davies, S., McCaughan, G.W., Increases in intrahepatic CD68 positive cells, MAC387 positive cells, and proinflammatory cytokines (particularly interleukin 18) in chronic hepatitis C infection. Gut 46 (2000), 260–269.
65. Xu, L., Yin, W., Sun, R., Wei, H., Tian, Z., Kupffer cell-derived IL-10 plays a key role in maintaining humoral immune tolerance in hepatitis B virus-persistent mice. Hepatology 59 (2014), 443–452.
66. Li, M., Sun, R., Xu, L., Yin, W., Chen, Y., Zheng, X., et al. Kupffer cells support hepatitis B virus-mediated CD8+ T cell exhaustion via hepatitis B core antigen-TLR2 interactions in mice. J Immunol 195 (2015), 3100–3109.
67. Tian, Y., Kuo, C.F., Akbari, O., Ou, J.H., Maternal-derived hepatitis B virus e antigen alters macrophage function in offspring to drive viral persistence after vertical transmission. Immunity 44 (2016), 1204–1214.
68. Baeck, C., Wehr, A., Karlmark, K.R., 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 61 (2012), 416–426.
69. Reid, D.T., Reyes, J.L., McDonald, B.A., Vo, T., Reimer, R.A., Eksteen, B., Kupffer cells undergo fundamental changes during the development of experimental NASH and are critical in initiating liver damage and inflammation. PLoS One, 11, 2016, e0159524.
70. Nakashima, H., Nakashima, M., Kinoshita, M., Ikarashi, M., Miyazaki, H., Hanaka, H., et al. Activation and increase of radio-sensitive CD11b+ recruited Kupffer cells/macrophages in diet-induced steatohepatitis in FGF5 deficient mice. Sci Rep, 6, 2016, 34466.
71. 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 302 (2012), G1310–G1321.
72. Zhang, X., Han, J., Man, K., Li, X., Du, J., Chu, E.S., et al. CXC chemokine receptor 3 promotes steatohepatitis in mice through mediating inflammatory cytokines, macrophages and autophagy. J Hepatol 64 (2016), 160–170.
73. 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 55 (2012), 898–909.
74. Seki, E., De Minicis, S., Gwak, G.Y., Kluwe, J., Inokuchi, S., Bursill, C.A., et al. CCR1 and CCR5 promote hepatic fibrosis in mice. J Clin Invest 119 (2009), 1858–1870.
75. Jindal, A., Bruzzi, S., Sutti, S., Locatelli, I., Bozzola, C., Paternostro, C., et al. Fat-laden macrophages modulate lobular inflammation in nonalcoholic steatohepatitis (NASH). Exp Mol Pathol 99 (2015), 155–162.
76. Hirsova, P., Ibrahim, S.H., Krishnan, A., Verma, V.K., Bronk, S.F., Werneburg, N.W., et al. Lipid-induced signaling causes release of inflammatory extracellular vesicles from hepatocytes. Gastroenterology 150 (2016), 956–967.
77. Kamari, Y., Shaish, A., Vax, E., Shemesh, S., Kandel-Kfir, M., Arbel, Y., et al. Lack of interleukin-1alpha or interleukin-1beta inhibits transformation of steatosis to steatohepatitis and liver fibrosis in hypercholesterolemic mice. J Hepatol 55 (2011), 1086–1094.
78. Wan, J., Benkdane, M., Teixeira-Clerc, F., Bonnafous, S., Louvet, A., Lafdil, F., et al. M2 Kupffer cells promote M1 Kupffer cell apoptosis: a protective mechanism against alcoholic and nonalcoholic fatty liver disease. Hepatology 59 (2014), 130–142.
79. Gadd, V.L., Skoien, R., Powell, E.E., Fagan, K.J., Winterford, C., Horsfall, L., et al. The portal inflammatory infiltrate and ductular reaction in human nonalcoholic fatty liver disease. Hepatology 59 (2014), 1393–1405.
80. Navarro, L.A., Wree, A., Povero, D., Berk, M.P., Eguchi, A., Ghosh, S., et al. Arginase 2 deficiency results in spontaneous steatohepatitis: a novel link between innate immune activation and hepatic de novo lipogenesis. J Hepatol 62 (2015), 412–420.
81. Wehr, A., Baeck, C., Heymann, F., Niemietz, P.M., Hammerich, L., Martin, C., et al. Chemokine receptor CXCR6-dependent hepatic NK T Cell accumulation promotes inflammation and liver fibrosis. J Immunol 190 (2013), 5226–5236.
82. Ehling, J., Bartneck, M., Wei, X., Gremse, F., Fech, V., Mockel, D., et al. CCL2-dependent infiltrating macrophages promote angiogenesis in progressive liver fibrosis. Gut 63 (2014), 1960–1971.
83. Ju, C., Mandrekar, P., Macrophages and alcohol-related liver inflammation. Alcohol Res 37 (2015), 251–262.
84. Suraweera, D.B., Weeratunga, A.N., Hu, R.W., Pandol, S.J., Hu, R., Alcoholic hepatitis: The pivotal role of Kupffer cells. World J Gastrointest Pathophysiol 6 (2015), 90–98.
85. 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 122 (2012), 3476–3489.
86. 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 96 (2014), 657–665.
87. 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 54 (2011), 2185–2197.
88. Calmus, Y., Poupon, R., Shaping macrophages function and innate immunity by bile acids: mechanisms and implication in cholestatic liver diseases. Clin Res Hepatol Gastroenterol 38 (2014), 550–556.
89. Gong, Z., Zhou, J., Zhao, S., Tian, C., Wang, P., Xu, C., et al. Chenodeoxycholic acid activates NLRP3 inflammasome and contributes to cholestatic liver fibrosis. Oncotarget, 2016.
90. Duwaerts, C.C., Gehring, S., Cheng, C.W., van Rooijen, N., Gregory, S.H., Contrasting responses of Kupffer cells and inflammatory mononuclear phagocytes to biliary obstruction in a mouse model of cholestatic liver injury. Liver Int 33 (2013), 255–265.
91. Keitel, V., Donner, M., Winandy, S., Kubitz, R., Haussinger, D., Expression and function of the bile acid receptor TGR5 in Kupffer cells. Biochem Biophys Res Commun 372 (2008), 78–84.
92. Pean, N., Doignon, I., Garcin, I., Besnard, A., Julien, B., Liu, B., et al. The receptor TGR5 protects the liver from bile acid overload during liver regeneration in mice. Hepatology 58 (2013), 1451–1460.
93. Guo, C., Xie, S., Chi, Z., Zhang, J., Liu, Y., Zhang, L., et al. Bile acids control inflammation and metabolic disorder through inhibition of NLRP3 inflammasome. Immunity 45 (2016), 802–816.
94. Oya, S., Yokoyama, Y., Kokuryo, T., Uno, M., Yamauchi, K., Nagino, M., Inhibition of Toll-like receptor 4 suppresses liver injury induced by biliary obstruction and subsequent intraportal lipopolysaccharide injection. Am J Physiol Gastrointest Liver Physiol 306 (2014), G244–G252.
95. Weiskirchen, R., Tacke, F., Liver fibrosis: from pathogenesis to novel therapies. Dig Dis 34 (2016), 410–422.
96. Loomba, R., Lawitz, E., Mantry, P.S., Jayakumar, S., Caldwell, S.H., Arnold, H., et al. GS-4997, an inhibitor of apoptosis signal-regulating kinase (ASK1), alone or in combination with Simtuzumab for the treatment of nonalcoholic steatohepatitis (NASH): a randomized, phase 2 trial. Hepatology 64 (2016), 1119A–1120A.
97. Sanyal, A.J., Ratziu, V., Harrison, S., Abdelmalek, M.F., Aithal, G.P., Caballeria, J., et al. Cenicriviroc placebo for the treatment of non-alcoholic steatohepatitis with liver fibrosis: Results from the Year 1 primary analysis of the Phase 2b CENTAUR study. Hepatology 64 (2016), 1118A–1119A.
98. Duffield, J.S., Forbes, S.J., Constandinou, C.M., Clay, S., Partolina, M., Vuthoori, S., et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest 115 (2005), 56–65.
99. Tosello-Trampont, A.C., Krueger, P., Narayanan, S., Landes, S.G., Leitinger, N., Hahn, Y.S., NKp46(+) natural killer cells attenuate metabolism-induced hepatic fibrosis by regulating macrophage activation in mice. Hepatology 63 (2016), 799–812.
100. Pradere, J.P., Kluwe, J., De Minicis, S., Jiao, J.J., Gwak, G.Y., Dapito, D.H., et al. Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice. Hepatology 58 (2013), 1461–1473.
101. Galastri, S., Zamara, E., Milani, S., Novo, E., Provenzano, A., Delogu, W., et al. Lack of CC chemokine ligand 2 differentially affects inflammation and fibrosis according to the genetic background in a murine model of steatohepatitis. Clin Sci 123 (2012), 459–471.
102. Seki, E., de Minicis, S., Inokuchi, S., Taura, K., Miyai, K., van Rooijen, N., et al. CCR2 promotes hepatic fibrosis in mice. Hepatology 50 (2009), 185–197.
103. Lodder, J., Denaes, T., Chobert, M.N., Wan, J., El-Benna, J., Pawlotsky, J.M., et al. Macrophage autophagy protects against liver fibrosis in mice. Autophagy 11 (2015), 1280–1292.
104. Gual, P., Gilgenkrantz, H., Lotersztajn, S., Autophagy in chronic liver diseases: the two faces of Janus. Am J Physiol Cell Physiol 312 (2017), C263–C273.
105. Karlmark, K.R., Zimmermann, H.W., Roderburg, C., Gassler, N., Wasmuth, H.E., Luedde, T., et al. The fractalkine receptor CX(3)CR1 protects against liver fibrosis by controlling differentiation and survival of infiltrating hepatic monocytes. Hepatology 52 (2010), 1769–1782.
106. Schneider, C., Teufel, A., Yevsa, T., Staib, F., Hohmeyer, A., Walenda, G., et al. Adaptive immunity suppresses formation and progression of diethylnitrosamine-induced liver cancer. Gut 61 (2012), 1733–1743.
107. 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 40 (2009), 381–389.
108. Li, X., Yao, W., Yuan, Y., Chen, P., Li, B., Li, J., et al. Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma. Gut 66 (2017), 157–167.
109. Yeung, O.W., Lo, C.M., Ling, C.C., Qi, X., Geng, W., Li, C.X., et al. Alternatively activated (M2) macrophages promote tumour growth and invasiveness in hepatocellular carcinoma. J Hepatol 62 (2015), 607–616.
110. Kuang, D.M., Zhao, Q., Peng, C., Xu, J., Zhang, J.P., Wu, C., et al. Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. J Exp Med 206 (2009), 1327–1337.
111. Wu, K., Kryczek, I., Chen, L., Zou, W., Welling, T.H., Kupffer cell suppression of CD8+ T cells in human hepatocellular carcinoma is mediated by B7–H1/programmed death-1 interactions. Cancer Res 69 (2009), 8067–8075.
112. Naugler, W.E., Sakurai, T., Kim, S., Maeda, S., Kim, K., Elsharkawy, A.M., et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317 (2007), 121–124.
113. Wan, S., Kuo, N., Kryczek, I., Zou, W., Welling, T.H., Myeloid cells in hepatocellular carcinoma. Hepatology 62 (2015), 1304–1312.
114. Wan, S., Zhao, E., Kryczek, I., Vatan, L., Sadovskaya, A., Ludema, G., et al. Tumor-associated macrophages produce interleukin 6 and signal via STAT3 to promote expansion of human hepatocellular carcinoma stem cells. Gastroenterology 147 (2014), 1393–1404.
115. Eggert, T., Wolter, K., Ji, J., Ma, C., Yevsa, T., Klotz, S., et al. Distinct functions of senescence-associated immune responses in liver tumor surveillance and tumor progression. Cancer Cell 30 (2016), 533–547.
116. Kang, T.W., Yevsa, T., Woller, N., Hoenicke, L., Wuestefeld, T., Dauch, D., et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479 (2011), 547–551.
117. Liedtke, C., Luedde, T., Sauerbruch, T., Scholten, D., Streetz, K., Tacke, F., et al. Experimental liver fibrosis research: update on animal models, legal issues and translational aspects. Fibrogenesis Tissue Repair, 6, 2013, 19.
118. Schlitzer, A., Schultze, J.L., Tissue-resident macrophages – How to humanize our knowledge. Immunol Cell Biol 95 (2017), 173–177.
119. Dapito, D.H., Mencin, A., Gwak, G.Y., Pradere, J.P., Jang, M.K., Mederacke, I., et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 21 (2012), 504–516.
120. Schneider, K.M., Bieghs, V., Heymann, F., Hu, W., Dreymueller, D., Liao, L., et al. CX3CR1 is a gatekeeper for intestinal barrier integrity in mice: Limiting steatohepatitis by maintaining intestinal homeostasis. Hepatology 62 (2015), 1405–1416.
121. Seki, E., De Minicis, S., Osterreicher, C.H., Kluwe, J., Osawa, Y., Brenner, D.A., et al. TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat Med 13 (2007), 1324–1332.
122. Szabo, G., Petrasek, J., Inflammasome activation and function in liver disease. Nat Rev Gastroenterol Hepatol 12 (2015), 387–400.
123. McNelis, J.C., Olefsky, J.M., Macrophages, immunity, and metabolic disease. Immunity 41 (2014), 36–48.
124. Marra, F., Tacke, F., Roles for chemokines in liver disease. Gastroenterology 147 (2014), 577–594, e571.
125. Lefebvre, E., Moyle, G., Reshef, R., Richman, L.P., Thompson, M., Hong, F., et al. Antifibrotic effects of the dual CCR2/CCR5 antagonist cenicriviroc in animal models of liver and kidney fibrosis. PLoS One, 11, 2016, e0158156.
126. Jalan, R., Fernandez, J., Wiest, R., Schnabl, B., Moreau, R., Angeli, P., et al. Bacterial infections in cirrhosis: a position statement based on the EASL Special Conference 2013. J Hepatol 60 (2014), 1310–1324.
127. Kedarisetty, C.K., Anand, L., Bhardwaj, A., Bhadoria, A.S., Kumar, G., Vyas, A.K., et al. Combination of granulocyte colony-stimulating factor and erythropoietin improves outcomes of patients with decompensated cirrhosis. Gastroenterology 148 (2015), 1362–1370, e1367.
128. Ergen, C., Heymann, F., Al Rawashdeh, W., Gremse, F., Bartneck, M., Panzer, U., et al. Targeting distinct myeloid cell populations in vivo using polymers, liposomes and microbubbles. Biomaterials 114 (2017), 106–120.
129. Melgert, B.N., Olinga, P., Van Der Laan, J.M., Weert, B., Cho, J., Schuppan, D., et al. Targeting dexamethasone to Kupffer cells: effects on liver inflammation and fibrosis in rats. Hepatology 34 (2001), 719–728.
130. Bartneck, M., Scheyda, K.M., Warzecha, K.T., Rizzo, L.Y., Hittatiya, K., Luedde, T., et al. Fluorescent cell-traceable dexamethasone-loaded liposomes for the treatment of inflammatory liver diseases. Biomaterials 37 (2015), 367–382.
131. Bartneck, M., Warzecha, K.T., Tacke, F., Therapeutic targeting of liver inflammation and fibrosis by nanomedicine. Hepatobiliary Surg Nutr 3 (2014), 364–376.
132. Traber, P.G., Zomer, E., Therapy of experimental NASH and fibrosis with galectin inhibitors. PLoS One, 8, 2013, e83481.
133. Forbes, S.J., Gupta, S., Dhawan, A., Cell therapy for liver disease: From liver transplantation to cell factory. J Hepatol 62 (2015), S157–S169.
134. Moore, J.K., Mackinnon, A.C., Wojtacha, D., Pope, C., Fraser, A.R., Burgoyne, P., et al. Phenotypic and functional characterization of macrophages with therapeutic potential generated from human cirrhotic monocytes in a cohort study. Cytotherapy 17 (2015), 1604–1616.
135. Thomas, J.A., Pope, C., Wojtacha, D., Robson, A.J., Gordon-Walker, T.T., Hartland, S., et al. Macrophage therapy for murine liver fibrosis recruits host effector cells improving fibrosis, regeneration, and function. Hepatology 53 (2011), 2003–2015.