Clinical Reviews in Allergy & Immunology

, Volume 54, Issue 2, pp 307–317 | Cite as

Myeloid Cells and Chronic Liver Disease: a Comprehensive Review

  • Min Lian
  • Carlo Selmi
  • M. Eric Gershwin
  • Xiong Ma


Myeloid cells play a major role in the sensitization to liver injury, particularly in chronic inflammatory liver diseases with a biliary or hepatocellular origin, and the interplay between myeloid cells and the liver may explain the increased incidence of hepatic osteodystrophy. The myeloid cell-liver axis involves several mature myeloid cells as well as immature or progenitor cells with the complexity of the liver immune microenvironment aggravating the mist of cell differentiation. The unique positioning of the liver at the junction of the peripheral and portal circulation systems underlines the interaction of myeloid cells and hepatic cells and leads to immune tolerance breakdown. We herein discuss the scenarios of different chronic liver diseases closely modulated by myeloid cells and illustrate the numerous potential targets, the understanding of which will ultimately steer the development of solid immunotherapeutic regimens. Ultimately, we are convinced that an adequate modulation of the liver microenvironment to modify the functional and quantitative characteristics of myeloid cells will be a successful approach to treating chronic liver diseases of different etiologies.


Myeloid cell Chronic inflammatory liver diseases Myeloid cell-liver axis Hepatic osteodystrophy 


Compliance with Ethical Standards

Ethical Approval and Informed Consent

No ethics issues are raised relevant to this review article.

Conflicts of Interest

The authors declare that they have no conflict of interest.


  1. 1.
    Sica A, Massarotti M (2017) Myeloid suppressor cells in cancer and autoimmunity. J Autoimmun 85:117–125CrossRefPubMedGoogle Scholar
  2. 2.
    David BA, Rezende RM, Antunes MM, Santos MM, Freitas Lopes MA, Diniz AB et al (2016) Combination of mass cytometry and imaging analysis reveals origin, location, and functional repopulation of liver myeloid cells in mice. Gastroenterology 151:1176–1191CrossRefPubMedGoogle Scholar
  3. 3.
    Doherty DG (2016) Immunity, tolerance and autoimmunity in the liver: a comprehensive review. J Autoimmun 66:60–75CrossRefPubMedGoogle Scholar
  4. 4.
    Liberal R, Krawitt EL, Vierling JM, Manns MP, Mieli-Vergani G, Vergani D (2016) Cutting edge issues in autoimmune hepatitis. J Autoimmun 75:6–19CrossRefPubMedGoogle Scholar
  5. 5.
    Horwood NJ (2016) Macrophage polarization and bone formation: a review. Clin Rev Allergy Immunol 51:79–86CrossRefPubMedGoogle Scholar
  6. 6.
    Humphrey MB, Nakamura MC (2016) A comprehensive review of immunoreceptor regulation of osteoclasts. Clin Rev Allergy Immunol 51:48–58PubMedCentralCrossRefPubMedGoogle Scholar
  7. 7.
    Jorge-Hernandez JA, Gonzalez-Reimers CE, Torres-Ramirez A, Santolaria-Fernandez F, Gonzalez-Garcia C, Batista-Lopez JN et al (1988) Bone changes in alcoholic liver cirrhosis. A histomorphometrical analysis of 52 cases. Dig Dis Sci 33:1089–1095CrossRefPubMedGoogle Scholar
  8. 8.
    Nussler AK, Wildemann B, Freude T, Litzka C, Soldo P, Friess H et al (2014) Chronic CCl4 intoxication causes liver and bone damage similar to the human pathology of hepatic osteodystrophy: a mouse model to analyse the liver-bone axis. Arch Toxicol 88:997–1006CrossRefPubMedGoogle Scholar
  9. 9.
    Nakano A, Kanda T, Abe H (1996) Bone changes and mineral metabolism disorders in rats with experimental liver cirrhosis. J Gastroenterol Hepatol 11:1143–1154CrossRefPubMedGoogle Scholar
  10. 10.
    Huang S, Kaw M, Harris MT, Ebraheim N, McInerney MF, Najjar SM et al (2010) Decreased osteoclastogenesis and high bone mass in mice with impaired insulin clearance due to liver-specific inactivation to CEACAM1. Bone 46:1138–1145PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    Collins AR, Gupte AA, Ji R, Ramirez MR, Minze LJ, Liu JZ et al (2012) Myeloid deletion of nuclear factor erythroid 2-related factor 2 increases atherosclerosis and liver injury. Arterioscler Thromb Vasc Biol 32:2839–2846PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.
    Weiskopf K, Schnorr PJ, Pang WW, Chao MP, Chhabra A, Seita J et al (2016) Myeloid cell origins, differentiation, and clinical implications. Microbiol Spectr 4(5).
  13. 13.
    Matsui T, Connolly JE, Michnevitz M, Chaussabel D, Yu CI, Glaser C et al (2009) CD2 distinguishes two subsets of human plasmacytoid dendritic cells with distinct phenotype and functions. J Immunol 182:6815–6823PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Ibrahim J, Nguyen AH, Rehman A, Ochi A, Jamal M, Graffeo CS et al (2012) Dendritic cell populations with different concentrations of lipid regulate tolerance and immunity in mouse and human liver. Gastroenterology 143:1061–1072PubMedCentralCrossRefPubMedGoogle Scholar
  15. 15.
    Lippens C, Duraes FV, Dubrot J, Brighouse D, Lacroix M, Irla M et al (2016) IDO-orchestrated crosstalk between pDCs and Tregs inhibits autoimmunity. J Autoimmun 75:39–49PubMedCentralCrossRefPubMedGoogle Scholar
  16. 16.
    Naito M, Hasegawa G, Ebe Y, Yamamoto T (2004) Differentiation and function of Kupffer cells. Med Electron Microsc 37:16–28CrossRefPubMedGoogle Scholar
  17. 17.
    Enomoto K, Nishikawa Y, Omori Y, Tokairin T, Yoshida M, Ohi N et al (2004) Cell biology and pathology of liver sinusoidal endothelial cells. Med Electron Microsc 37:208–215CrossRefPubMedGoogle Scholar
  18. 18.
    Nakatani K, Kaneda K, Seki S, Nakajima Y (2004) Pit cells as liver-associated natural killer cells: morphology and function. Med Electron Microsc 37:29–36CrossRefPubMedGoogle Scholar
  19. 19.
    Senoo H (2004) Structure and function of hepatic stellate cells. Med Electron Microsc 37:3–15CrossRefPubMedGoogle Scholar
  20. 20.
    Yoneyama H, Ichida T (2005) Recruitment of dendritic cells to pathological niches in inflamed liver. Med Mol Morphol 38:136–141CrossRefPubMedGoogle Scholar
  21. 21.
    Tsuji N, Kawada N, Ikeda K, Kinoshita H, Kaneda K (1997) Immunohistochemical and ultrastructural analyses of in situ activation of hepatic stellate cells around Propionibacterium acnes-induced granulomas in the rat liver. J Submicrosc Cytol Pathol 29:125–133PubMedGoogle Scholar
  22. 22.
    Ogata M, Zhang Y, Wang Y, Itakura M, Zhang YY, Harada A et al (1999) Chemotactic response toward chemokines and its regulation by transforming growth factor-beta1 of murine bone marrow hematopoietic progenitor cell-derived different subset of dendritic cells. Blood 93:3225–3232PubMedGoogle Scholar
  23. 23.
    Fujioka N, Mukaida N, Harada A, Akiyama M, Kasahara T, Kuno K et al (1995) Preparation of specific antibodies against murine IL-1ra and the establishment of IL-1ra as an endogenous regulator of bacteria-induced fulminant hepatitis in mice. J Leukoc Biol 58:90–98CrossRefPubMedGoogle Scholar
  24. 24.
    Yoneyama H, Harada A, Imai T, Baba M, Yoshie O, Zhang Y et al (1998) Pivotal role of TARC, a CC chemokine, in bacteria-induced fulminant hepatic failure in mice. J Clin Invest 102:1933–1941PubMedCentralCrossRefPubMedGoogle Scholar
  25. 25.
    Yoneyama H, Narumi S, Zhang Y, Murai M, Baggiolini M, Lanzavecchia A et al (2002) Pivotal role of dendritic cell-derived CXCL10 in the retention of T helper cell 1 lymphocytes in secondary lymph nodes. J Exp Med 195:1257–1266PubMedCentralCrossRefPubMedGoogle Scholar
  26. 26.
    Lukacs-Kornek V, Schuppan D (2013) Dendritic cells in liver injury and fibrosis: shortcomings and promises. J Hepatol 59:1124–1126CrossRefPubMedGoogle Scholar
  27. 27.
    Bleier JI, Katz SC, Chaudhry UI, Pillarisetty VG, Kingham TP 3rd, Shah AB et al (2006) Biliary obstruction selectively expands and activates liver myeloid dendritic cells. J Immunol 176:7189–7195CrossRefPubMedGoogle Scholar
  28. 28.
    Connolly MK, Bedrosian AS, Mallen-St Clair J, Mitchell AP, Ibrahim J, Stroud A et al (2009) In liver fibrosis, dendritic cells govern hepatic inflammation in mice via TNF-alpha. J Clin Invest 119:3213–3225PubMedCentralPubMedGoogle Scholar
  29. 29.
    Aloman C, Tacke F (2010) Dendritic cells in liver fibrosis: conductor of the inflammatory orchestra? Hepatology 51:1070–1072CrossRefPubMedGoogle Scholar
  30. 30.
    Ikeda A, Aoki N, Kido M, Iwamoto S, Nishiura H, Maruoka R et al (2014) Progression of autoimmune hepatitis is mediated by IL-18-producing dendritic cells and hepatic CXCL9 expression in mice. Hepatology 60:224–236CrossRefPubMedGoogle Scholar
  31. 31.
    Velazquez VM, Hon H, Ibegbu C, Knechtle SJ, Kirk AD, Grakoui A (2012) Hepatic enrichment and activation of myeloid dendritic cells during chronic hepatitis C virus infection. Hepatology 56:2071–2081PubMedCentralCrossRefPubMedGoogle Scholar
  32. 32.
    Henning JR, Graffeo CS, Rehman A, Fallon NC, Zambirinis CP, Ochi A et al (2013) Dendritic cells limit fibroinflammatory injury in nonalcoholic steatohepatitis in mice. Hepatology 58:589–602PubMedCentralCrossRefPubMedGoogle Scholar
  33. 33.
    Sutti S, Locatelli I, Bruzzi S, Jindal A, Vacchiano M, Bozzola C et al (2015) CX3CR1-expressing inflammatory dendritic cells contribute to the progression of steatohepatitis. Clin Sci (Lond) 129:797–808CrossRefGoogle Scholar
  34. 34.
    Morell M, Varela N, Maranon C (2017) Myeloid populations in systemic autoimmune diseases. Clin Rev Allergy Immunol 53:198–218CrossRefPubMedGoogle Scholar
  35. 35.
    Karlmark KR, Weiskirchen R, Zimmermann HW, Gassler N, Ginhoux F, Weber C et al (2009) Hepatic recruitment of the inflammatory Gr1+ monocyte subset upon liver injury promotes hepatic fibrosis. Hepatology 50:261–274CrossRefPubMedGoogle Scholar
  36. 36.
    Ziegler-Heitbrock L, Ancuta P, Crowe S, Dalod M, Grau V, Hart DN et al (2010) Nomenclature of monocytes and dendritic cells in blood. Blood 116:e74–e80CrossRefPubMedGoogle Scholar
  37. 37.
    Grage-Griebenow E, Flad HD, Ernst M (2001) Heterogeneity of human peripheral blood monocyte subsets. J Leukoc Biol 69:11–20PubMedGoogle Scholar
  38. 38.
    Bataller R, Brenner DA (2005) Liver fibrosis. J Clin Invest 115:209–218PubMedCentralCrossRefPubMedGoogle Scholar
  39. 39.
    Heymann F, Trautwein C, Tacke F (2009) Monocytes and macrophages as cellular targets in liver fibrosis. Inflamm Allergy Drug Targets 8:307–318CrossRefPubMedGoogle Scholar
  40. 40.
    Liaskou E, Zimmermann HW, Li KK, Oo YH, Suresh S, Stamataki Z et al (2013) Monocyte subsets in human liver disease show distinct phenotypic and functional characteristics. Hepatology 57:385–398CrossRefPubMedGoogle Scholar
  41. 41.
    Zimmermann HW, Bruns T, Weston CJ, Curbishley SM, Liaskou E, Li KK et al (2016) Bidirectional transendothelial migration of monocytes across hepatic sinusoidal endothelium shapes monocyte differentiation and regulates the balance between immunity and tolerance in liver. Hepatology 63:233–246CrossRefPubMedGoogle Scholar
  42. 42.
    Thomson AW, Knolle PA (2010) Antigen-presenting cell function in the tolerogenic liver environment. Nat Rev Immunol 10:753–766CrossRefPubMedGoogle Scholar
  43. 43.
    Mai P, Yang L, Tian L, Wang L, Jia S, Zhang Y et al (2015) Endocannabinoid system contributes to liver injury and inflammation by activation of bone marrow-derived monocytes/macrophages in a CB1-dependent manner. J Immunol 195:3390–3401CrossRefPubMedGoogle Scholar
  44. 44.
    McMahan RH, Wang XX, Cheng LL, Krisko T, Smith M, El Kasmi K et al (2013) Bile acid receptor activation modulates hepatic monocyte activity and improves nonalcoholic fatty liver disease. J Biol Chem 288:11761–11770PubMedCentralCrossRefPubMedGoogle Scholar
  45. 45.
    Nahrendorf M, Swirski FK, Aikawa E, Stangenberg L, Wurdinger T, Figueiredo JL et al (2007) The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J Exp Med 204:3037–3047PubMedCentralCrossRefPubMedGoogle Scholar
  46. 46.
    Dal-Secco D, Wang J, Zeng Z, Kolaczkowska E, Wong CH, Petri B et al (2015) A dynamic spectrum of monocytes arising from the in situ reprogramming of CCR2+ monocytes at a site of sterile injury. J Exp Med 212:447–456PubMedCentralCrossRefPubMedGoogle Scholar
  47. 47.
    Miura K, Yang L, van Rooijen N, Ohnishi H, Seki E (2012) Hepatic recruitment of macrophages promotes nonalcoholic steatohepatitis through CCR2. Am J Physiol Gastrointest Liver Physiol 302:G1310–G1321PubMedCentralCrossRefPubMedGoogle Scholar
  48. 48.
    Mossanen JC, Krenkel O, Ergen C, Govaere O, Liepelt A, Puengel T et al (2016) Chemokine (C-C motif) receptor 2-positive monocytes aggravate the early phase of acetaminophen-induced acute liver injury. Hepatology 64:1667–1682CrossRefPubMedGoogle Scholar
  49. 49.
    Karlmark KR, Zimmermann HW, Roderburg C, Gassler N, Wasmuth HE, Luedde T et al (2010) The fractalkine receptor CX(3)CR1 protects against liver fibrosis by controlling differentiation and survival of infiltrating hepatic monocytes. Hepatology 52:1769–1782CrossRefPubMedGoogle Scholar
  50. 50.
    Landsman L, Bar-On L, Zernecke A, Kim KW, Krauthgamer R, Shagdarsuren E et al (2009) CX3CR1 is required for monocyte homeostasis and atherogenesis by promoting cell survival. Blood 113:963–972CrossRefPubMedGoogle Scholar
  51. 51.
    Aspinall AI, Curbishley SM, Lalor PF, Weston CJ, Blahova M, Liaskou E et al (2010) CX(3)CR1 and vascular adhesion protein-1-dependent recruitment of CD16(+) monocytes across human liver sinusoidal endothelium. Hepatology 51:2030–2039PubMedCentralCrossRefPubMedGoogle Scholar
  52. 52.
    Ji J, Eggert T, Budhu A, Forgues M, Takai A, Dang H et al (2015) Hepatic stellate cell and monocyte interaction contributes to poor prognosis in hepatocellular carcinoma. Hepatology 62:481–495PubMedCentralCrossRefPubMedGoogle Scholar
  53. 53.
    Elsegood CL, Chan CW, Degli-Esposti MA, Wikstrom ME, Domenichini A, Lazarus K et al (2015) Kupffer cell-monocyte communication is essential for initiating murine liver progenitor cell-mediated liver regeneration. Hepatology 62:1272–1284CrossRefPubMedGoogle Scholar
  54. 54.
    Melgar-Lesmes P, Edelman ER (2015) Monocyte-endothelial cell interactions in the regulation of vascular sprouting and liver regeneration in mouse. J Hepatol 63:917–925PubMedCentralCrossRefPubMedGoogle Scholar
  55. 55.
    Ramachandran P, Pellicoro A, Vernon MA, Boulter L, Aucott RL, Ali A et al (2012) Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis. Proc Natl Acad Sci U S A 109:E3186–E3195PubMedCentralCrossRefPubMedGoogle Scholar
  56. 56.
    Sica A, Invernizzi P, Mantovani A (2014) Macrophage plasticity and polarization in liver homeostasis and pathology. Hepatology 59:2034–2042CrossRefPubMedGoogle Scholar
  57. 57.
    Schulz C, Gomez Perdiguero E, Chorro L, Szabo-Rogers H, Cagnard N, Kierdorf K et al (2012) A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336:86–90CrossRefPubMedGoogle Scholar
  58. 58.
    Hoeffel G, Chen J, Lavin Y, Low D, Almeida FF, See P et al (2015) C-Myb(+) erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages. Immunity 42:665–678PubMedCentralCrossRefPubMedGoogle Scholar
  59. 59.
    Sica A, Mantovani A (2012) Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 122:787–795PubMedCentralCrossRefPubMedGoogle Scholar
  60. 60.
    Nakazawa D, Shida H, Kusunoki Y, Miyoshi A, Nishio S, Tomaru U et al (2016) The responses of macrophages in interaction with neutrophils that undergo NETosis. J Autoimmun 67:19–28CrossRefPubMedGoogle Scholar
  61. 61.
    Matsuda M, Tsurusaki S, Miyata N, Saijou E, Okochi H, Miyajima A et al (2017) Oncostatin M causes liver fibrosis by regulating cooperation between hepatic stellate cells and macrophages in mice. Hepatology 67(1):296–312Google Scholar
  62. 62.
    Amiya T, Nakamoto N, Chu PS, Teratani T, Nakajima H, Fukuchi Y et al (2016) Bone marrow-derived macrophages distinct from tissue-resident macrophages play a pivotal role in concanavalin A-induced murine liver injury via CCR9 axis. Sci Rep 6:35146PubMedCentralCrossRefPubMedGoogle Scholar
  63. 63.
    Lages CS, Simmons J, Maddox A, Jones K, Karns R, Sheridan R et al (2017) The dendritic cell-T helper 17-macrophage axis controls cholangiocyte injury and disease progression in murine and human biliary atresia. Hepatology 65:174–188CrossRefPubMedGoogle Scholar
  64. 64.
    Meng F, Wang K, Aoyama T, Grivennikov SI, Paik Y, Scholten D et al (2012) Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice. Gastroenterology 143:765–776 e3PubMedCentralCrossRefPubMedGoogle Scholar
  65. 65.
    Cheng Y, Tian Y, Xia J, Wu X, Yang Y, Li X et al (2017) The role of PTEN in regulation of hepatic macrophages activation and function in progression and reversal of liver fibrosis. Toxicol Appl Pharmacol 317:51–62CrossRefPubMedGoogle Scholar
  66. 66.
    Bain CC, Bravo-Blas A, Scott CL, Perdiguero EG, Geissmann F, Henri S et al (2014) Constant replenishment from circulating monocytes maintains the macrophage pool in the intestine of adult mice. Nat Immunol 15:929–937PubMedCentralCrossRefPubMedGoogle Scholar
  67. 67.
    Tamoutounour S, Guilliams M, Montanana Sanchis F, Liu H, Terhorst D, Malosse C et al (2013) Origins and functional specialization of macrophages and of conventional and monocyte-derived dendritic cells in mouse skin. Immunity 39:925–938CrossRefPubMedGoogle Scholar
  68. 68.
    Davies LC, Rosas M, Jenkins SJ, Liao CT, Scurr MJ, Brombacher F et al (2013) Distinct bone marrow-derived and tissue-resident macrophage lineages proliferate at key stages during inflammation. Nat Commun 4:1886CrossRefPubMedGoogle Scholar
  69. 69.
    Epelman S, Lavine KJ, Beaudin AE, Sojka DK, Carrero JA, Calderon B et al (2014) Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation. Immunity 40:91–104PubMedCentralCrossRefPubMedGoogle Scholar
  70. 70.
    Ju C, Tacke F (2016) Hepatic macrophages in homeostasis and liver diseases: from pathogenesis to novel therapeutic strategies. Cell Mol Immunol 13:316–327PubMedCentralCrossRefPubMedGoogle Scholar
  71. 71.
    Scott CL, Zheng F, De Baetselier P, Martens L, Saeys Y, De Prijck S et al (2016) Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells. Nat Commun 7:10321PubMedCentralCrossRefPubMedGoogle Scholar
  72. 72.
    Bleriot C, Dupuis T, Jouvion G, Eberl G, Disson O, Lecuit M (2015) Liver-resident macrophage necroptosis orchestrates type 1 microbicidal inflammation and type-2-mediated tissue repair during bacterial infection. Immunity 42:145–158CrossRefPubMedGoogle Scholar
  73. 73.
    Nascimento M, Huang SC, Smith A, Everts B, Lam W, Bassity E et al (2014) Ly6Chi monocyte recruitment is responsible for Th2 associated host-protective macrophage accumulation in liver inflammation due to schistosomiasis. PLoS Pathog 10:e1004282PubMedCentralCrossRefPubMedGoogle Scholar
  74. 74.
    Nishijima H, Kajimoto T, Matsuoka Y, Mouri Y, Morimoto J, Matsumoto M et al (2017) Paradoxical development of polymyositis-like autoimmunity through augmented expression of autoimmune regulator (AIRE). J Autoimmun 86:75–92Google Scholar
  75. 75.
    Jordan KR, Amaria RN, Ramirez O, Callihan EB, Gao D, Borakove M et al (2013) Myeloid-derived suppressor cells are associated with disease progression and decreased overall survival in advanced-stage melanoma patients. Cancer Immunol Immunother 62:1711–1722PubMedCentralCrossRefPubMedGoogle Scholar
  76. 76.
    Ham B, Wang N, D'Costa Z, Fernandez MC, Bourdeau F, Auguste P et al (2015) TNF receptor-2 facilitates an immunosuppressive microenvironment in the liver to promote the colonization and growth of hepatic metastases. Cancer Res 75:5235–5247CrossRefPubMedGoogle Scholar
  77. 77.
    Zhang G, Huang H, Zhu Y, Yu G, Gao X, Xu Y et al (2015) A novel subset of B7-H3+CD14+HLA-DR−/low myeloid-derived suppressor cells are associated with progression of human NSCLC. Oncoimmunology 4:e977164PubMedCentralCrossRefPubMedGoogle Scholar
  78. 78.
    Lei A, Yang Q, Li X, Chen H, Shi M, Xiao Q et al (2016) Atorvastatin promotes the expansion of myeloid-derived suppressor cells and attenuates murine colitis. Immunology 149:432–446PubMedCentralCrossRefPubMedGoogle Scholar
  79. 79.
    Park MJ, Lee SH, Kim EK, Lee EJ, Park SH, Kwok SK et al (2016) Myeloid-derived suppressor cells induce the expansion of regulatory B cells and ameliorate autoimmunity in the Sanroque mouse model of systemic lupus erythematosus. Arthritis Rheumatol 68:2717–2727CrossRefPubMedGoogle Scholar
  80. 80.
    Hammerich L, Tacke F (2015) Emerging roles of myeloid derived suppressor cells in hepatic inflammation and fibrosis. World J Gastrointest Pathophysiol 6:43–50PubMedCentralCrossRefPubMedGoogle Scholar
  81. 81.
    Bronte V, Brandau S, Chen SH, Colombo MP, Frey AB, Greten TF et al (2016) Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun 7:12150PubMedCentralCrossRefPubMedGoogle Scholar
  82. 82.
    Jeong Ryu S, Ju JM, Kim W, Bum Kim M, Hee Oh K, Sup Lee D et al (2015) Alleviation of skin inflammation after Lin(−) cell transplantation correlates with their differentiation into myeloid-derived suppressor cells. Sci Rep 5:14663PubMedCentralCrossRefPubMedGoogle Scholar
  83. 83.
    Mandruzzato S, Brandau S, Britten CM, Bronte V, Damuzzo V, Gouttefangeas C et al (2016) Toward harmonized phenotyping of human myeloid-derived suppressor cells by flow cytometry: results from an interim study. Cancer Immunol Immunother 65:161–169PubMedCentralCrossRefPubMedGoogle Scholar
  84. 84.
    Parker KH, Beury DW, Ostrand-Rosenberg S (2015) Myeloid-derived suppressor cells: critical cells driving immune suppression in the tumor microenvironment. Adv Cancer Res 128:95–139PubMedCentralCrossRefPubMedGoogle Scholar
  85. 85.
    Chou HS, Hsieh CC, Yang HR, Wang L, Arakawa Y, Brown K et al (2011) Hepatic stellate cells regulate immune response by way of induction of myeloid suppressor cells in mice. Hepatology 53:1007–1019PubMedCentralCrossRefPubMedGoogle Scholar
  86. 86.
    Yen BL, Yen ML, Hsu PJ, Liu KJ, Wang CJ, Bai CH et al (2013) Multipotent human mesenchymal stromal cells mediate expansion of myeloid-derived suppressor cells via hepatocyte growth factor/c-met and STAT3. Stem Cell Reports 1:139–151PubMedCentralCrossRefPubMedGoogle Scholar
  87. 87.
    Goh CC, Roggerson KM, Lee HC, Golden-Mason L, Rosen HR, Hahn YS (2016) Hepatitis C virus-induced myeloid-derived suppressor cells suppress NK cell IFN-gamma production by altering cellular metabolism via arginase-1. J Immunol 196:2283–2292PubMedCentralCrossRefPubMedGoogle Scholar
  88. 88.
    Trikha P, Carson WE 3rd (2014) Signaling pathways involved in MDSC regulation. Biochim Biophys Acta 1846:55–65PubMedCentralPubMedGoogle Scholar
  89. 89.
    Hsu SH, Wang B, Kota J, Yu J, Costinean S, Kutay H et al (2012) Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver. J Clin Invest 122:2871–2883PubMedCentralCrossRefPubMedGoogle Scholar
  90. 90.
    Cantoni C, Cignarella F, Ghezzi L, Mikesell B, Bollman B, Berrien-Elliott MM et al (2017) Mir-223 regulates the number and function of myeloid-derived suppressor cells in multiple sclerosis and experimental autoimmune encephalomyelitis. Acta Neuropathol 133:61–77CrossRefPubMedGoogle Scholar
  91. 91.
    Wang J, Cao X, Zhao J, Zhao H, Wei J, Li Q et al (2017) Critical roles of conventional dendritic cells in promoting T cell-dependent hepatitis through regulating natural killer T cells. Clin Exp Immunol 188:127–137CrossRefPubMedGoogle Scholar
  92. 92.
    Gronbaek H, Kreutzfeldt M, Kazankov K, Jessen N, Sandahl T, Hamilton-Dutoit S et al (2016) Single-centre experience of the macrophage activation marker soluble (s)CD163—associations with disease activity and treatment response in patients with autoimmune hepatitis. Aliment Pharmacol Ther 44:1062–1070CrossRefPubMedGoogle Scholar
  93. 93.
    Lafdil F, Wang H, Park O, Zhang W, Moritoki Y, Yin S et al (2009) Myeloid STAT3 inhibits T cell-mediated hepatitis by regulating T helper 1 cytokine and interleukin-17 production. Gastroenterology 137:2125–35 e1–2PubMedCentralCrossRefPubMedGoogle Scholar
  94. 94.
    Hardtke-Wolenski M, Dywicki J, Fischer K, Hapke M, Sievers M, Schlue J et al (2017) The influence of genetic predisposition and autoimmune hepatitis inducing antigens in disease development. J Autoimmun 78:39–45CrossRefPubMedGoogle Scholar
  95. 95.
    Hudspeth K, Donadon M, Cimino M, Pontarini E, Tentorio P, Preti M et al (2016) Human liver-resident CD56(bright)/CD16(neg) NK cells are retained within hepatic sinusoids via the engagement of CCR5 and CXCR6 pathways. J Autoimmun 66:40–50CrossRefPubMedGoogle Scholar
  96. 96.
    Diao W, Jin F, Wang B, Zhang CY, Chen J, Zen K et al (2014) The protective role of myeloid-derived suppressor cells in concanavalin A-induced hepatic injury. Protein Cell 5:714–724PubMedCentralCrossRefPubMedGoogle Scholar
  97. 97.
    Zhang H, Liu Y, Bian Z, Huang S, Han X, You Z et al (2014) The critical role of myeloid-derived suppressor cells and FXR activation in immune-mediated liver injury. J Autoimmun 53:55–66CrossRefPubMedGoogle Scholar
  98. 98.
    Hammerich L, Warzecha KT, Stefkova M, Bartneck M, Ohl K, Gassler N et al (2015) Cyclic adenosine monophosphate-responsive element modulator alpha overexpression impairs function of hepatic myeloid-derived suppressor cells and aggravates immune-mediated hepatitis in mice. Hepatology 61:990–1002CrossRefPubMedGoogle Scholar
  99. 99.
    Wang Q, Yang F, Miao Q, Krawitt EL, Gershwin ME, Ma X (2016) The clinical phenotypes of autoimmune hepatitis: a comprehensive review. J Autoimmun 66:98–107CrossRefPubMedGoogle Scholar
  100. 100.
    You Z, Wang Q, Bian Z, Liu Y, Han X, Peng Y et al (2012) The immunopathology of liver granulomas in primary biliary cirrhosis. J Autoimmun 39:216–221PubMedCentralCrossRefPubMedGoogle Scholar
  101. 101.
    Poupon R (2010) Primary biliary cirrhosis: A 2010 update. J Hepatol 52:745–758CrossRefPubMedGoogle Scholar
  102. 102.
    Tian J, Yang G, Chen HY, Hsu DK, Tomilov A, Olson KA et al (2016) Galectin-3 regulates inflammasome activation in cholestatic liver injury. FASEB J 30:4202–4213PubMedCentralCrossRefPubMedGoogle Scholar
  103. 103.
    Allina J, Hu B, Sullivan DM, Fiel MI, Thung SN, Bronk SF et al (2006) T cell targeting and phagocytosis of apoptotic biliary epithelial cells in primary biliary cirrhosis. J Autoimmun 27:232–241CrossRefPubMedGoogle Scholar
  104. 104.
    Lleo A, Invernizzi P (2013) Apotopes and innate immune system: novel players in the primary biliary cirrhosis scenario. Dig Liver Dis 45:630–636CrossRefPubMedGoogle Scholar
  105. 105.
    Lleo A, Bowlus CL, Yang GX, Invernizzi P, Podda M, Van de Water J et al (2010) Biliary apotopes and anti-mitochondrial antibodies activate innate immune responses in primary biliary cirrhosis. Hepatology 52:987–998PubMedCentralCrossRefPubMedGoogle Scholar
  106. 106.
    Hisamoto S, Shimoda S, Harada K, Iwasaka S, Onohara S, Chong Y et al (2016) Hydrophobic bile acids suppress expression of AE2 in biliary epithelial cells and induce bile duct inflammation in primary biliary cholangitis. J Autoimmun 75:150–160CrossRefPubMedGoogle Scholar
  107. 107.
    Webb GJ, Hirschfield GM (2016) Using GWAS to identify genetic predisposition in hepatic autoimmunity. J Autoimmun 66:25–39CrossRefPubMedGoogle Scholar
  108. 108.
    Hsueh YH, Chang YN, Loh CE, Gershwin ME, Chuang YH (2016) AAV-IL-22 modifies liver chemokine activity and ameliorates portal inflammation in murine autoimmune cholangitis. J Autoimmun 66:89–97CrossRefPubMedGoogle Scholar
  109. 109.
    Chawla A, Nguyen KD, Goh YP (2011) Macrophage-mediated inflammation in metabolic disease. Nat Rev Immunol 11:738–749PubMedCentralCrossRefPubMedGoogle Scholar
  110. 110.
    Lumeng CN, Bodzin JL, Saltiel AR (2007) Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 117:175–184PubMedCentralCrossRefPubMedGoogle Scholar
  111. 111.
    Obstfeld AE, Sugaru E, Thearle M, Francisco AM, Gayet C, Ginsberg HN et al (2010) C-C chemokine receptor 2 (CCR2) regulates the hepatic recruitment of myeloid cells that promote obesity-induced hepatic steatosis. Diabetes 59:916–925PubMedCentralCrossRefPubMedGoogle Scholar
  112. 112.
    Chen Z, Shen H, Sun C, Yin L, Tang F, Zheng P et al (2015) Myeloid cell TRAF3 promotes metabolic inflammation, insulin resistance, and hepatic steatosis in obesity. Am J Physiol Endocrinol Metab 308:E460–E469PubMedCentralCrossRefPubMedGoogle Scholar
  113. 113.
    Muller P, Messmer M, Bayer M, Pfeilschifter JM, Hintermann E, Christen U (2016) Non-alcoholic fatty liver disease (NAFLD) potentiates autoimmune hepatitis in the CYP2D6 mouse model. J Autoimmun 69:51–58CrossRefPubMedGoogle Scholar
  114. 114.
    Baeck C, Wehr A, Karlmark KR, Heymann F, Vucur M, Gassler N et al (2012) Pharmacological inhibition of the chemokine CCL2 (MCP-1) diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury. Gut 61:416–426CrossRefPubMedGoogle Scholar
  115. 115.
    Spadaro O, Camell CD, Bosurgi L, Nguyen KY, Youm YH, Rothlin CV et al (2017) IGF1 shapes macrophage activation in response to immunometabolic challenge. Cell Rep 19:225–234PubMedCentralCrossRefPubMedGoogle Scholar
  116. 116.
    Deng ZB, Liu Y, Liu C, Xiang X, Wang J, Cheng Z et al (2009) Immature myeloid cells induced by a high-fat diet contribute to liver inflammation. Hepatology 50:1412–1420PubMedCentralCrossRefPubMedGoogle Scholar
  117. 117.
    Chen L, Zhang Z, Chen W, Zhang Z, Li Y, Shi M et al (2007) B7-H1 up-regulation on myeloid dendritic cells significantly suppresses T cell immune function in patients with chronic hepatitis B. J Immunol 178:6634–6641CrossRefPubMedGoogle Scholar
  118. 118.
    Li X, Liu X, Tian L, Chen Y (2016) Cytokine-mediated immunopathogenesis of hepatitis B virus infections. Clin Rev Allergy Immunol 50:41–54CrossRefPubMedGoogle Scholar
  119. 119.
    Pallett LJ, Gill US, Quaglia A, Sinclair LV, Jover-Cobos M, Schurich A et al (2015) Metabolic regulation of hepatitis B immunopathology by myeloid-derived suppressor cells. Nat Med 21:591–600PubMedCentralCrossRefPubMedGoogle Scholar
  120. 120.
    Huang LR, Wohlleber D, Reisinger F, Jenne CN, Cheng RL, Abdullah Z et al (2013) Intrahepatic myeloid-cell aggregates enable local proliferation of CD8(+) T cells and successful immunotherapy against chronic viral liver infection. Nat Immunol 14:574–583CrossRefPubMedGoogle Scholar
  121. 121.
    Yoshio S, Kanto T, Kuroda S, Matsubara T, Higashitani K, Kakita N et al (2013) Human blood dendritic cell antigen 3 (BDCA3)(+) dendritic cells are a potent producer of interferon-lambda in response to hepatitis C virus. Hepatology 57:1705–1715CrossRefPubMedGoogle Scholar
  122. 122.
    Ju C, Colgan SP, Eltzschig HK (2016) Hypoxia-inducible factors as molecular targets for liver diseases. J Mol Med (Berl) 94:613–627CrossRefGoogle Scholar
  123. 123.
    Copple BL, Kaska S, Wentling C (2012) Hypoxia-inducible factor activation in myeloid cells contributes to the development of liver fibrosis in cholestatic mice. J Pharmacol Exp Ther 341:307–316PubMedCentralCrossRefPubMedGoogle Scholar
  124. 124.
    Gaia S, Smedile A, Omede P, Olivero A, Sanavio F, Balzola F et al (2006) Feasibility and safety of G-CSF administration to induce bone marrow-derived cells mobilization in patients with end stage liver disease. J Hepatol 45:13–19CrossRefPubMedGoogle Scholar
  125. 125.
    Bernsmeier C, Triantafyllou E, Brenig R, Lebosse FJ, Singanayagam A, Patel VC et al (2017) CD14+CD15-HLA-DR- myeloid-derived suppressor cells impair antimicrobial responses in patients with acute-on-chronic liver failure. Gut.
  126. 126.
    Neuberger J (2016) An update on liver transplantation: a critical review. J Autoimmun 66:51–59CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018
corrected publication [March/2018]

Authors and Affiliations

  • Min Lian
    • 1
  • Carlo Selmi
    • 2
    • 3
  • M. Eric Gershwin
    • 4
  • Xiong Ma
    • 1
  1. 1.Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversityShanghai Institute of Digestive DiseaseShanghaiChina
  2. 2.Division of Rheumatology and Clinical ImmunologyHumanitas Research HospitalRozzanoItaly
  3. 3.BIOMETRA DepartmentUniversity of MilanMilanItaly
  4. 4.Division of Rheumatology, Department of Medicine, Allergy and Clinical ImmunologyUniversity of California at DavisDavisUSA

Personalised recommendations