Advertisement

Targeting hepatic macrophages to treat liver diseases

  • Frank Tacke
    Correspondence
    Corresponding author. Address: Department of Medicine III, RWTH-University Hospital Aachen, Aachen, Germany.
    Affiliations
    Department of Medicine III, University Hospital Aachen, Aachen, Germany
    Search for articles by this author
Published:March 04, 2017DOI:https://doi.org/10.1016/j.jhep.2017.02.026

      Summary

      Our view on liver macrophages in the context of health and disease has been reformed by the recognition of a remarkable heterogeneity of phagocytes in the liver. Liver macrophages consist of ontogenically distinct populations termed Kupffer cells and monocyte-derived macrophages. Kupffer cells are self-renewing, resident and principally non-migratory phagocytes, serving as sentinels for liver homeostasis. Liver injury triggers Kupffer cell activation, leading to inflammatory cytokine and chemokine release. This fosters the infiltration of monocytes into the liver, which give rise to large numbers of inflammatory monocyte-derived macrophages. Liver macrophages are very plastic and adapt their phenotype according to signals derived from the hepatic microenvironment (e.g. danger signals, fatty acids, phagocytosis of cellular debris), which explains their manifold and even opposing functions during disease. These central functions include the perpetuation of inflammation and hepatocyte injury, activation of hepatic stellate cells with subsequent fibrogenesis, and support of tumor development by angiogenesis and T cell suppression. If liver injury ceases, specific molecular signals trigger hepatic macrophages to switch their phenotype towards reparative phagocytes that promote tissue repair and regression of fibrosis. Novel strategies to treat liver disease aim at targeting macrophages. These interventions modulate Kupffer cell activation (e.g. via gut-liver axis or inflammasome formation), monocyte recruitment (e.g. via inhibiting chemokine pathways like CCR2 or CCL2) or macrophage polarization and differentiation (e.g. by nanoparticles). Evidence from mouse models and early clinical studies in patients with non-alcoholic steatohepatitis and fibrosis support the notion that pathogenic macrophage subsets can be successfully translated into novel treatment options for patients with liver disease.

      Lay summary

      Macrophages (Greek for “big eaters”) are a frequent non-parenchymal cell type of the liver that ensures homeostasis, antimicrobial defense and proper metabolism. However, liver macrophages consist of different subtypes regarding their ontogeny (developmental origin), differentiation and function. Understanding this heterogeneity and the critical regulation of inflammation, fibrosis and cancer by macrophage subsets opens promising new options for treating liver diseases.

      Graphical abstract

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of Hepatology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Heymann F.
        • Tacke F.
        Immunology in the liver–from homeostasis to disease.
        Nat Rev Gastroenterol Hepatol. 2016; 13: 88-110
        • 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. 2011; 10: 2
        • Tacke F.
        • Zimmermann H.W.
        Macrophage heterogeneity in liver injury and fibrosis.
        J Hepatol. 2014; 60: 1090-1096
        • von Kupffer K.W.
        Über Sternzellen der Leber.
        Arch Mikroskop Anat. 1876; 12: 353-358
        • Gomez Perdiguero E.
        • Klapproth K.
        • Schulz C.
        • Busch K.
        • Azzoni E.
        • Crozet L.
        • et al.
        Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors.
        Nature. 2015; 518: 547-551
        • Mass E.
        • Ballesteros I.
        • Farlik M.
        • Halbritter F.
        • Gunther P.
        • Crozet L.
        • et al.
        Specification of tissue-resident macrophages during organogenesis.
        Science. 2016; 353
        • 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. 2015; 42: 665-678
        • Varol C.
        • Mildner A.
        • Jung S.
        Macrophages: development and tissue specialization.
        Ann Rev Immunol. 2015; 33: 643-675
        • 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. 2015; 212: 447-456
        • Wang J.
        • Kubes P.
        A reservoir of mature cavity macrophages that can rapidly invade visceral organs to affect tissue repair.
        Cell. 2016; 165: 668-678
        • 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
        • 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. 2016; 151: 1176-1191
        • Helmy K.Y.
        • Katschke Jr., K.J.
        • 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. 2006; 124: 915-927
        • 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. 2016; 20: 99-106
        • 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. 2016; 213: 1141-1151
        • Strnad P.
        • Tacke F.
        • Koch A.
        • Trautwein C.
        Liver – guardian, modifier and target of sepsis.
        Nat Rev Gastroenterol Hepatol. 2017; 14: 55-66
        • 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. 2010; 115: e10-e19
        • 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. 2016; 64: 1667-1682
        • 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. 2007; 317: 666-670
        • Serbina N.V.
        • Pamer E.G.
        Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2.
        Nat Immunol. 2006; 7: 311-317
        • 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. 2009; 325: 612-616
        • 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. 2009; 50: 261-274
        • 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. 2016; 22: 945-951
        • Crispe I.N.
        Liver antigen-presenting cells.
        J Hepatol. 2011; 54: 357-365
        • 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. 2016; 34: 93-119
        • 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. 2016; 7: 10321
        • 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. 2016; 65: 758-768
        • 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. 2007; 110: 4077-4085
        • 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. 2012; 109: E3186-E3195
        • 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. 2013; 57: 385-398
        • 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. 2010; 5 (e11049)
        • 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. 2014; 60: 135-142
        • Murray P.J.
        Macrophage polarization.
        Ann Rev Physiol. 2017; 79: 541-566
        • 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. 2014; 59: 1060-1072
        • 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
        • 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. 2014; 40: 274-288
        • 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. 2016; 63: 1310-1324
        • 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. 2014; 41: 14-20
        • Ju C.
        • Tacke F.
        Hepatic macrophages in homeostasis and liver diseases: from pathogenesis to novel therapeutic strategies.
        Cell Mol Immunol. 2016; 13: 316-327
        • 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. 2015; 89: 4809-4817
        • 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. 2011; 11: 1563-1569
        • Bernal W.
        • Wendon J.
        Acute liver failure.
        N Engl J Med. 2013; 369: 2525-2534
        • Krenkel O.
        • Mossanen J.C.
        • Tacke F.
        Immune mechanisms in acetaminophen-induced acute liver failure.
        Hepatobiliary Surg Nutr. 2014; 3: 331-343
        • 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. 2015; 125: 539-550
        • 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
        • Holt M.P.
        • Cheng L.
        • Ju C.
        Identification and characterization of infiltrating macrophages in acetaminophen-induced liver injury.
        J Leukoc Biol. 2008; 84: 1410-1421
        • 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. 2012; 56: 735-746
        • 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. 2017; 45: 443-454
        • 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. 2002; 35: 289-298
        • 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. 2002; 15: 1504-1513
        • 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. 2013; 86: 836-843
        • 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. 2015; 149: 1896-1909
        • 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. 2014; 59: 1564-1576
        • 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. 2013; 110: 6542-6547
        • 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. 2012; 18: 572-579
        • 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. 2016; 11 (e0166094)
        • Boltjes A.
        • Movita D.
        • Boonstra A.
        • Woltman A.M.
        The role of Kupffer cells in hepatitis B and hepatitis C virus infections.
        J Hepatol. 2014; 61: 660-671
        • 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. 2015; 211: 1268-1278
        • 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. 2008; 205: 233-244
        • 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. 2013; 87: 12284-12290
        • 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
        • 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
        • 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. 2010; 138: 305-314
        • 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. 2000; 46: 260-269
        • 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. 2014; 59: 443-452
        • 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. 2015; 195: 3100-3109
        • 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. 2016; 44: 1204-1214
        • 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. 2012; 61: 416-426
        • 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. 2016; 11 (e0159524)
        • 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. 2016; 6: 34466
        • Miura K.
        • Yang L.
        • van Rooijen N.
        • Ohnishi H.
        • Seki E.
        Hepatic recruitment of macrophages promotes nonalcoholic steatohepatitis through CCR2.
        Am J Physiol Gastrointest Liver Physiol. 2012; 302: G1310-G1321
        • 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. 2016; 64: 160-170
        • 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
        • 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. 2009; 119: 1858-1870
        • 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. 2015; 99: 155-162
        • 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. 2016; 150: 956-967
        • 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. 2011; 55: 1086-1094
        • 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. 2014; 59: 130-142
        • 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. 2014; 59: 1393-1405
        • 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. 2015; 62: 412-420
        • 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. 2013; 190: 5226-5236
        • 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. 2014; 63: 1960-1971
        • Ju C.
        • Mandrekar P.
        Macrophages and alcohol-related liver inflammation.
        Alcohol Res. 2015; 37: 251-262
        • 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. 2015; 6: 90-98
        • 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
        • 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
        • 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
        • Calmus Y.
        • Poupon R.
        Shaping macrophages function and innate immunity by bile acids: mechanisms and implication in cholestatic liver diseases.
        Clin Res Hepatol Gastroenterol. 2014; 38: 550-556
        • 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;
        • 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. 2013; 33: 255-265
        • 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. 2008; 372: 78-84
        • 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. 2013; 58: 1451-1460
        • 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. 2016; 45: 802-816
        • 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. 2014; 306: G244-G252
        • Weiskirchen R.
        • Tacke F.
        Liver fibrosis: from pathogenesis to novel therapies.
        Dig Dis. 2016; 34: 410-422
        • 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. 2016; 64: 1119A-1120A
        • 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. 2016; 64: 1118A-1119A
        • 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. 2005; 115: 56-65
        • 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. 2016; 63: 799-812
        • 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. 2013; 58: 1461-1473
        • 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. 2012; 123: 459-471
        • Seki E.
        • de Minicis S.
        • Inokuchi S.
        • Taura K.
        • Miyai K.
        • van Rooijen N.
        • et al.
        CCR2 promotes hepatic fibrosis in mice.
        Hepatology. 2009; 50: 185-197
        • 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. 2015; 11: 1280-1292
        • Gual P.
        • Gilgenkrantz H.
        • Lotersztajn S.
        Autophagy in chronic liver diseases: the two faces of Janus.
        Am J Physiol Cell Physiol. 2017; 312: C263-C273
        • 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. 2010; 52: 1769-1782
        • 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. 2012; 61: 1733-1743
        • 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
        • 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. 2017; 66: 157-167
        • 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. 2015; 62: 607-616
        • 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. 2009; 206: 1327-1337
        • 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. 2009; 69: 8067-8075
        • 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. 2007; 317: 121-124
        • Wan S.
        • Kuo N.
        • Kryczek I.
        • Zou W.
        • Welling T.H.
        Myeloid cells in hepatocellular carcinoma.
        Hepatology. 2015; 62: 1304-1312
        • 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. 2014; 147: 1393-1404
        • 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. 2016; 30: 533-547
        • 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. 2011; 479: 547-551
        • 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. 2013; 6: 19
        • Schlitzer A.
        • Schultze J.L.
        Tissue-resident macrophages – How to humanize our knowledge.
        Immunol Cell Biol. 2017; 95: 173-177
        • 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. 2012; 21: 504-516
        • 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. 2015; 62: 1405-1416
        • 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. 2007; 13: 1324-1332
        • Szabo G.
        • Petrasek J.
        Inflammasome activation and function in liver disease.
        Nat Rev Gastroenterol Hepatol. 2015; 12: 387-400
        • McNelis J.C.
        • Olefsky J.M.
        Macrophages, immunity, and metabolic disease.
        Immunity. 2014; 41: 36-48
        • Marra F.
        • Tacke F.
        Roles for chemokines in liver disease.
        Gastroenterology. 2014; 147 (e571): 577-594
        • 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. 2016; 11 (e0158156)
        • 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. 2014; 60: 1310-1324
        • 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. 2015; 148 (e1367): 1362-1370
        • 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. 2017; 114: 106-120
        • 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. 2001; 34: 719-728
        • 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. 2015; 37: 367-382
        • Bartneck M.
        • Warzecha K.T.
        • Tacke F.
        Therapeutic targeting of liver inflammation and fibrosis by nanomedicine.
        Hepatobiliary Surg Nutr. 2014; 3: 364-376
        • Traber P.G.
        • Zomer E.
        Therapy of experimental NASH and fibrosis with galectin inhibitors.
        PLoS One. 2013; 8 (e83481)
        • Forbes S.J.
        • Gupta S.
        • Dhawan A.
        Cell therapy for liver disease: From liver transplantation to cell factory.
        J Hepatol. 2015; 62: S157-S169
        • 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. 2015; 17: 1604-1616
        • 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. 2011; 53: 2003-2015