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

Nature Reviews Gastroenterology and Hepatology

Volumn 16, Issue 3, 2019, Pages 145-159

  Kazankov, Konstantin ^a,b   Jørgensen, Simon Mark Dahl ^a   Thomsen, Karen Louise ^a   Møller, Holger Jon ^a   Vilstrup, Hendrik ^a   George, Jacob ^c   Schuppan, Detlef ^d,e   Grønbæk, Henning ^a  

^a AARHUS UNIVERSITY HOSPITAL   (Denmark)

^b RANDERS REGIONAL HOSPITAL   (Denmark)

^c UNIVERSITY OF SYDNEY   (Australia)

^d JOHANNES GUTENBERG UNIVERSITY   (Germany)

^e HARVARD MEDICAL SCHOOL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ADIPONECTIN; CENICRIVIROC; CHOLESTEROL; DEXAMETHASONE; ELAFIBRANOR; ENDOTOXIN; FATTY ACID; GALECTIN 3; GLUCOCORTICOID RECEPTOR; LEPTIN; LIRAGLUTIDE; OBETICHOLIC ACID; PENTOXIFYLLINE; PIOGLITAZONE; REACTIVE OXYGEN METABOLITE; SELONSERTIB; SEMAGLUTIDE; TUMOR NECROSIS FACTOR;

ADIPOSE TISSUE; BACTERIAL TRANSLOCATION; CELL MEMBRANE DEPOLARIZATION; DISEASE COURSE; DISEASE SEVERITY; DRUG TARGETING; HEPATITIS; HUMAN; INSULIN RESISTANCE; INTESTINE FLORA; INTESTINE MUCOSA PERMEABILITY; LIPOAPOPTOSIS; LIVER CELL; LIVER CELL DAMAGE; LIVER FIBROSIS; MACROPHAGE ACTIVATION; MACROPHAGE FUNCTION; MONOCYTE MACROPHAGE PRECURSOR CELL; NONALCOHOLIC FATTY LIVER; NONHUMAN; NUTRIENT CONTENT; PATHOGENESIS; PRIORITY JOURNAL; REVIEW; STEATOSIS; VISCERA; ANIMAL; DISEASE EXACERBATION; IMMUNOLOGY; LIVER; MACROPHAGE; PATHOPHYSIOLOGY; PHYSIOLOGY;

ANIMALS; DISEASE PROGRESSION; HUMANS; LIVER; MACROPHAGES; NON-ALCOHOLIC FATTY LIVER DISEASE;

EID: 85057330496     PISSN: 17595045     EISSN: 17595053     Source Type: Journal    
DOI: 10.1038/s41575-018-0082-x     Document Type: Review

References (200)

1. Vernon, G., Baranova, A. & Younossi, Z. M. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment. Pharmacol. Ther. 34, 274–285 (2011).
2. Wong, R. J. et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology 148, 547–555 (2015).
3. Angulo, P. et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 149, 389–397 (2015).
4. Schuppan, D., Surabattula, R. & Wang, X. Y. Determinants of fibrosis progression and regression in NASH. J. Hepatol. 68, 238–250 (2018). This comprehensive review provides an insight into the epidemiology, key mechanisms, diagnostic tools and treatment options for liver fibrosis in NAFLD.
5. Tilg, H. & Moschen, A. R. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 52, 1836–1846 (2010).
6. Maher, J. J., Leon, P. & Ryan, J. C. Beyond insulin resistance: innate immunity in nonalcoholic steatohepatitis. Hepatology 48, 670–678 (2008).
7. Kolios, G., Valatas, V. & Kouroumalis, E. Role of Kupffer cells in the pathogenesis of liver disease. World J. Gastroenterol. 12, 7413–7420 (2006).
8. Gomez Perdiguero, E. et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518, 547–551 (2015).
9. Krenkel, O. & Tacke, F. Liver macrophages in tissue homeostasis and disease. Nat. Rev. Immunol. 17, 306–321 (2017).
10. Mass, E. et al. Specification of tissue-resident macrophages during organogenesis. Science 353, aaf4238 (2016).
11. Scott, C. L. et al. Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells. Nat. Commun. 7, 10321 (2016).
12. Heymann, F. & Tacke, F. Immunology in the liver — from homeostasis to disease. Nat. Rev. Gastroenterol. Hepatol. 13, 88–110 (2016).
13. Tacke, F. Targeting hepatic macrophages to treat liver diseases. J. Hepatol. 66, 1300–1312 (2017).
14. Heymann, F. et al. Liver inflammation abrogates immunological tolerance induced by Kupffer cells. Hepatology 62, 279–291 (2015).
15. Tacke, F. & Zimmermann, H. W. Macrophage heterogeneity in liver injury and fibrosis. J. Hepatol. 60, 1090–1096 (2014).
16. + monocyte subset upon liver injury promotes hepatic fibrosis. Hepatology 50, 261–274 (2009).
17. Mehal, W. Z. & Schuppan, D. Antifibrotic therapies in the liver. Semin. Liver Dis. 35, 184–198 (2015).
18. Pellicoro, A., Ramachandran, P., Iredale, J. P. & Fallowfield, J. A. Liver fibrosis and repair: immune regulation of wound healing in a solid organ. Nat. Rev. Immunol. 14, 181–194 (2014).
19. Ramachandran, P. 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, E3186–E3195 (2012).
20. Duffield, J. S. et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J. Clin. Invest. 115, 56–65 (2005).
21. Eming, S. A., Wynn, T. A. & Martin, P. Inflammation and metabolism in tissue repair and regeneration. Science 356, 1026–1030 (2017).
22. Murray, P. J. et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41, 14–20 (2014). This consensus paper provides an important overview of macrophages in terms of their origin, factors contributing to macrophage activation and the markers to describe different macrophage phenotypes.
23. Popov, Y. et al. Macrophage-mediated phagocytosis of apoptotic cholangiocytes contributes to reversal of experimental biliary fibrosis. Am. J. Physiol. Gastrointest. Liver Physiol. 298, G323–G334 (2010).
24. Schuppan, D. & Kim, Y. O. Evolving therapies for liver fibrosis. J. Clin. Invest. 123, 1887–1901 (2013).
25. Wang, X. et al. Gliptins suppress inflammatory macrophage activation to mitigate inflammation, fibrosis, oxidative stress, and vascular dysfunction in models of nonalcoholic steatohepatitis and liver fibrosis. Antioxid. Redox Signal. 28, 87–109 (2018).
26. Weng, S. Y. et al. IL-4 receptor α signaling through macrophages differentially regulates liver fibrosis progression and reversal. EBioMedicine 29, 92–103 (2018).
27. Ding, T. et al. High tumor-infiltrating macrophage density predicts poor prognosis in patients with primary hepatocellular carcinoma after resection. Hum. Pathol. 40, 381–389 (2009).
28. Kuang, D. M. et al. Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. J. Exp. Med. 206, 1327–1337 (2009).
29. Wan, S. et al. Tumor-associated macrophages produce interleukin 6 and signal via STAT3 to promote expansion of human hepatocellular carcinoma stem cells. Gastroenterology 147, 1393–1404 (2014).
30. Kazankov, K. et al. Macrophage activation marker soluble CD163 may predict disease progression in hepatocellular carcinoma. Scand. J. Clin. Lab. Invest. 76, 64–73 (2016).
31. Waidmann, O. et al. Diagnostic and prognostic significance of cell death and macrophage activation markers in patients with hepatocellular carcinoma. J. Hepatol. 59, 769–779 (2013).
32. Li, X. et al. Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma. Gut 66, 157–167 (2017).
33. Park, J. W., Jeong, G., Kim, S. J., Kim, M. K. & Park, S. M. Predictors reflecting the pathological severity of non-alcoholic fatty liver disease: comprehensive study of clinical and immunohistochemical findings in younger Asian patients. J. Gastroenterol. Hepatol. 22, 491–497 (2007).
34. Lotowska, J. M., Sobaniec-Lotowska, M. E. & Lebensztejn, D. M. The role of Kupffer cells in the morphogenesis of nonalcoholic steatohepatitis — ultrastructural findings. The first report in pediatric patients. Scand. J. Gastroenterol. 48, 352–357 (2013).
35. Gadd, V. L. et al. The portal inflammatory infiltrate and ductular reaction in human nonalcoholic fatty liver disease. Hepatology 59, 1393–1405 (2014). This clinical study emphasizes the role of macrophages in NAFLD, demonstrating that portal macrophage infiltration is an early event in the development of NASH and is associated with progressive disease.
36. Itoh, M. et al. Hepatic crown-like structure: a unique histological feature in non-alcoholic steatohepatitis in mice and humans. PLOS ONE 8, e82163 (2013).
37. Rensen, S. S. et al. Increased hepatic myeloperoxidase activity in obese subjects with nonalcoholic steatohepatitis. Am. J. Pathol. 175, 1473–1482 (2009).
38. Ioannou, G. N., Haigh, W. G., Thorning, D. & Savard, C. Hepatic cholesterol crystals and crown-like structures distinguish NASH from simple steatosis. J. Lipid Res. 54, 1326–1334 (2013).
39. Kiki, I. et al. Effect of high fat diet on the volume of liver and quantitative feature of Kupffer cells in the female rat: a stereological and ultrastructural study. Obes. Surg. 17, 1381–1388 (2007).
40. Lanthier, N. et al. Kupffer cell activation is a causal factor for hepatic insulin resistance. Am. J. Physiol. Gastrointest. Liver Physiol. 298, G107–G116 (2010).
41. Tosello-Trampont, A. C., Landes, S. G., Nguyen, V., Novobrantseva, T. I. & Hahn, Y. S. Kuppfer cells trigger nonalcoholic steatohepatitis development in diet-induced mouse model through tumor necrosis factor-α production. J. Biol. Chem. 287, 40161–40172 (2012). This experimental study demonstrates that Kupffer cells producing TNF are instrumental in the early phases of steatohepatitis by initiating inflammation and promoting monocyte recruitment.
42. Fontana, L. et al. Aging promotes the development of diet-induced murine steatohepatitis but not steatosis. Hepatology 57, 995–1004 (2013).
43. de Meijer, V. E., Sverdlov, D. Y., Le, H. D., Popov, Y. & Puder, M. Tissue-specific differences in inflammatory infiltrate and matrix metalloproteinase expression in adipose tissue and liver of mice with diet-induced obesity. Hepatol. Res. 42, 601–610 (2012).
44. Clementi, A. H., Gaudy, A. M., van, R. N., Pierce, R. H. & Mooney, R. A. Loss of Kupffer cells in diet-induced obesity is associated with increased hepatic steatosis, STAT3 signaling, and further decreases in insulin signaling. Biochim. Biophys. Acta 1792, 1062–1072 (2009).
45. Ni, Y. et al. Astaxanthin prevents and reverses diet-induced insulin resistance and steatohepatitis in mice: a comparison with vitamin E. Sci. Rep. 5, 17192 (2015).
46. Larter, C. Z. & Yeh, M. M. Animal models of NASH: getting both pathology and metabolic context right. J. Gastroenterol. Hepatol. 23, 1635–1648 (2008).
47. Lau, J. K., Zhang, X. & Yu, J. Animal models of non-alcoholic fatty liver disease: current perspectives and recent advances. J. Pathol. 241, 36–44 (2017).
48. Van Herck, M. A., Vonghia, L. & Francque, S. M. Animal models of nonalcoholic fatty liver disease — a starter’s guide. Nutrients 9, 1072 (2017).
49. Huang, W. et al. Depletion of liver Kupffer cells prevents the development of diet-induced hepatic steatosis and insulin resistance. Diabetes 59, 347–357 (2010).
50. Neyrinck, A. M. et al. Critical role of Kupffer cells in the management of diet-induced diabetes and obesity. Biochem. Biophys. Res. Commun. 385, 351–356 (2009).
51. Stienstra, R. et al. Kupffer cells promote hepatic steatosis via interleukin-1β-dependent suppression of peroxisome proliferator-activated receptor α activity. Hepatology 51, 511–522 (2010). This study using a mouse model of NAFLD highlights the role of Kupffer cells in the development of hepatic steatosis via secretion of IL-1β.
52. Stienstra, R. et al. Peroxisome proliferator-activated receptor α protects against obesity-induced hepatic inflammation. Endocrinology 148, 2753–2763 (2007).
53. Miura, K., Yang, L., van, R. N., Ohnishi, H. & Seki, E. Hepatic recruitment of macrophages promotes nonalcoholic steatohepatitis through CCR2. Am. J. Physiol. Gastrointest. Liver Physiol. 302, G1310–G1321 (2012).
54. Rivera, C. A. et al. Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis. J. Hepatol. 47, 571–579 (2007).
55. Mills, C. D., Kincaid, K., Alt, J. M., Heilman, M. J. & Hill, A. M. M-1/M-2 macrophages and the Th1/Th2 paradigm. J. Immunol. 164, 6166–6173 (2000).
56. Maina, V. et al. Bias in macrophage activation pattern influences non-alcoholic steatohepatitis (NASH) in mice. Clin. Sci. 122, 545–553 (2012).
57. Wan, J. et al. M2 Kupffer cells promote M1 Kupffer cell apoptosis: a protective mechanism against alcoholic and nonalcoholic fatty liver disease. Hepatology 59, 130–142 (2014). This study suggests that the anti-inflammatory macrophage phenotype might be beneficial in NAFLD.
58. Papackova, Z. et al. Kupffer cells ameliorate hepatic insulin resistance induced by high-fat diet rich in monounsaturated fatty acids: the evidence for the involvement of alternatively activated macrophages. Nutr. Metab. 9, 22 (2012).
59. Odegaard, J. I. et al. Alternative M2 activation of Kupffer cells by PPARδ ameliorates obesity-induced insulin resistance. Cell Metab. 7, 496–507 (2008).
60. Jindal, A. et al. Fat-laden macrophages modulate lobular inflammation in nonalcoholic steatohepatitis (NASH). Exp. Mol. Pathol. 99, 155–162 (2015).
61. Hart, K. M. et al. Type 2 immunity is protective in metabolic disease but exacerbates NAFLD collaboratively with TGF-β. Sci. Transl Med. 9, eaal3694 (2017).
62. Svendsen, P. et al. Antibody-directed glucocorticoid targeting to CD163 in M2-type macrophages attenuates fructose-induced liver inflammatory changes. Mol. Ther. Methods Clin. Dev. 4, 50–61 (2017). This study demonstrates that direct targeting of macrophages by a conjugated glucocorticoid improves liver histology in a fructose-induced rat model of NASH, suggesting this approach as a potential treatment for steatohepatitis.
63. Deshmane, S. L., Kremlev, S., Amini, S. & Sawaya, B. E. Monocyte chemoattractant protein-1 (MCP-1): an overview. J. Interferon Cytokine Res. 29, 313–326 (2009).
64. Obstfeld, A. E. et al. C-C chemokine receptor 2 (CCR2) regulates the hepatic recruitment of myeloid cells that promote obesity-induced hepatic steatosis. Diabetes 59, 916–925 (2010).
65. Morinaga, H. et al. Characterization of distinct subpopulations of hepatic macrophages in HFD/obese mice. Diabetes 64, 1120–1130 (2015). This mouse study highlights that Kupffer cells and monocyte-derived macrophages in NAFLD are morphologically different, comprising two distinct subpopulations of hepatic macrophages.
66. Krenkel, O. et al. Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis. Hepatology 67, 1270–1283 (2018).
67. Deng, Z. B. et al. Immature myeloid cells induced by a high-fat diet contribute to liver inflammation. Hepatology 50, 1412–1420 (2009).
68. Yang, S. J., IglayReger, H. B., Kadouh, H. C. & Bodary, P. F. Inhibition of the chemokine (C-C motif) ligand 2/chemokine (C-C motif) receptor 2 pathway attenuates hyperglycaemia and inflammation in a mouse model of hepatic steatosis and lipoatrophy. Diabetologia 52, 972–981 (2009).
69. Weisberg, S. P. et al. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J. Clin. Invest. 116, 115–124 (2006). This study demonstrates that inhibition of CCR2 improves insulin sensitivity and hepatic steatosis, highlighting the distinctive role of monocyte-derived macrophages in obesity and NAFLD.
70. Baeck, C. et al. Pharmacological inhibition of the chemokine CCL2 (MCP-1) diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury. Gut 61, 416–426 (2012).
71. Frasinariu, O. E., Ceccarelli, S., Alisi, A., Moraru, E. & Nobili, V. Gut-liver axis and fibrosis in nonalcoholic fatty liver disease: an input for novel therapies. Dig. Liver Dis. 45, 543–551 (2013).
72. Budick-Harmelin, N. et al. Triglycerides potentiate the inflammatory response in rat Kupffer cells. Antioxid. Redox Signal. 10, 2009–2022 (2008).
73. Kawaratani, H. et al. Innate immune reactivity of the liver in rats fed a choline-deficient L-amino-acid-defined diet. World J. Gastroenterol. 14, 6655–6661 (2008).
74. Leroux, A. et al. Toxic lipids stored by Kupffer cells correlates with their pro-inflammatory phenotype at an early stage of steatohepatitis. J. Hepatol. 57, 141–149 (2012). This mouse study demonstrates that Kupffer cells contain lipid droplets and that these lipid-laden Kupffer cells are prone to pro-inflammatory activation, providing a link between lipotoxicity and macrophage activation.
75. Kudo, H. et al. Lipopolysaccharide triggered TNF-α-induced hepatocyte apoptosis in a murine non-alcoholic steatohepatitis model. J. Hepatol. 51, 168–175 (2009).
76. Ye, D. et al. Toll-like receptor-4 mediates obesity-induced non-alcoholic steatohepatitis through activation of X-box binding protein-1 in mice. Gut 61, 1058–1067 (2012).
77. Vespasiani-Gentilucci, U. et al. Hepatic toll-like receptor 4 expression is associated with portal inflammation and fibrosis in patients with NAFLD. Liver Int. 35, 569–581 (2015).
78. Spruss, A. et al. Toll-like receptor 4 is involved in the development of fructose-induced hepatic steatosis in mice. Hepatology 50, 1094–1104 (2009).
79. Wagnerberger, S. et al. Toll-like receptors 1–9 are elevated in livers with fructose-induced hepatic steatosis. Br. J. Nutr. 107, 1727–1738 (2012).
80. Miura, K. et al. Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1β in mice. Gastroenterology 139, 323–334 (2010).
81. Li, L. et al. Nuclear factor high-mobility group box 1 mediating the activation of Toll-like receptor 4 signaling in hepatocytes in the early stage of nonalcoholic fatty liver disease in mice. Hepatology 54, 1620–1630 (2011).
82. Jia, L. et al. Hepatocyte Toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance. Nat. Commun. 5, 3878 (2014).
83. Neuschwander-Tetri, B. A. Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites. Hepatology 52, 774–788 (2010).
84. Lee, J. Y., Sohn, K. H., Rhee, S. H. & Hwang, D. Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4. J. Biol. Chem. 276, 16683–16689 (2001).
85. Lee, J. Y. et al. Reciprocal modulation of Toll-like receptor-4 signaling pathways involving MyD88 and phosphatidylinositol 3-kinase/AKT by saturated and polyunsaturated fatty acids. J. Biol. Chem. 278, 37041–37051 (2003).
86. Snodgrass, R. G., Huang, S., Choi, I. W., Rutledge, J. C. & Hwang, D. H. Inflammasome-mediated secretion of IL-1β in human monocytes through TLR2 activation; modulation by dietary fatty acids. J. Immunol. 191, 4337–4347 (2013).
87. Miura, K. et al. Toll-like receptor 2 and palmitic acid cooperatively contribute to the development of nonalcoholic steatohepatitis through inflammasome activation in mice. Hepatology 57, 577–589 (2013). This study demonstrates cooperative activation of Kupffer cells by palmitate and TLR2, supporting the mechanism of macrophage activation by FFAs.
88. Kim, S. Y. et al. Pro-inflammatory hepatic macrophages generate ROS through NADPH oxidase 2 via endocytosis of monomeric TLR4-MD2 complex. Nat. Commun. 8, 2247 (2017).
89. Pal, D. et al. Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nat. Med. 18, 1279–1285 (2012).
90. Bohm, T. et al. Food-derived peroxidized fatty acids may trigger hepatic inflammation: a novel hypothesis to explain steatohepatitis. J. Hepatol. 59, 563–570 (2013).
91. Obara, N. et al. Possible involvement and the mechanisms of excess trans-fatty acid consumption in severe NAFLD in mice. J. Hepatol. 53, 326–334 (2010).
92. Musso, G., Gambino, R. & Cassader, M. Cholesterol metabolism and the pathogenesis of non-alcoholic steatohepatitis. Prog. Lipid Res. 52, 175–191 (2013).
93. Ioannou, G. N. et al. Cholesterol crystallization within hepatocyte lipid droplets and its role in murine NASH. J. Lipid Res. 58, 1067–1079 (2017). This study demonstrates that Kupffer cells process cholesterol crystals, which lead to Kupffer cell activation in association with the development of NASH, highlighting macrophage activation by cholesterol.
94. Kunjathoor, V. V. et al. Scavenger receptors class A-I/II and CD36 are the principal receptors responsible for the uptake of modified low density lipoprotein leading to lipid loading in macrophages. J. Biol. Chem. 277, 49982–49988 (2002).
95. Bieghs, V. et al. Trapping of oxidized LDL in lysosomes of Kupffer cells is a trigger for hepatic inflammation. Liver Int. 33, 1056–1061 (2013).
96. Bieghs, V. et al. Role of scavenger receptor A and CD36 in diet-induced nonalcoholic steatohepatitis in hyperlipidemic mice. Gastroenterology 138, 2477–2486, 2486 (2010).
97. Bieghs, V. et al. Internalization of modified lipids by CD36 and SR-A leads to hepatic inflammation and lysosomal cholesterol storage in Kupffer cells. PLOS ONE 7, e34378 (2012).
98. Bieghs, V. et al. Specific immunization strategies against oxidized low-density lipoprotein: a novel way to reduce nonalcoholic steatohepatitis in mice. Hepatology 56, 894–903 (2012).
99. Bieghs, V. et al. The cholesterol derivative 27-hydroxycholesterol reduces steatohepatitis in mice. Gastroenterology 144, 167–178 (2013).
100. Pan, X. et al. Adipogenic changes of hepatocytes in a high-fat diet-induced fatty liver mice model and non-alcoholic fatty liver disease patients. Endocrine 48, 834–847 (2015).
101. Canbay, A. et al. Kupffer cell engulfment of apoptotic bodies stimulates death ligand and cytokine expression. Hepatology 38, 1188–1198 (2003).
102. Miller, Y. I. et al. Oxidation-specific epitopes are danger-associated molecular patterns recognized by pattern recognition receptors of innate immunity. Circ. Res. 108, 235–248 (2011).
103. Bartneck, M. et al. Histidine-rich glycoprotein promotes macrophage activation and inflammation in chronic liver disease. Hepatology 63, 1310–1324 (2016).
104. Hirsova, P. et al. Lipid-induced signaling causes release of inflammatory extracellular vesicles from hepatocytes. Gastroenterology 150, 956–967 (2016).
105. Tomita, K. et al. CXCL10-mediates macrophage, but not other innate immune cells-associated inflammation in murine nonalcoholic steatohepatitis. Sci. Rep. 6, 28786 (2016).
106. Ibrahim, S. H. et al. Mixed lineage kinase 3 mediates release of C-X-C motif ligand 10-bearing chemotactic extracellular vesicles from lipotoxic hepatocytes. Hepatology 63, 731–744 (2016).
107. Cannito, S. et al. Microvesicles released from fat-laden cells promote activation of hepatocellular NLRP3 inflammasome: a pro-inflammatory link between lipotoxicity and non-alcoholic steatohepatitis. PLOS ONE 12, e0172575 (2017).
108. Di Naso, F. C. et al. Obesity depresses the anti-inflammatory HSP70 pathway, contributing to NAFLD progression. Obesity 23, 120–129 (2015).
109. Fujita, N. & Takei, Y. Iron overload in nonalcoholic steatohepatitis. Adv. Clin. Chem. 55, 105–132 (2011).
110. Otogawa, K. et al. Erythrophagocytosis by liver macrophages (Kupffer cells) promotes oxidative stress, inflammation, and fibrosis in a rabbit model of steatohepatitis: implications for the pathogenesis of human nonalcoholic steatohepatitis. Am. J. Pathol. 170, 967–980 (2007).
111. Fujita, N. et al. Iron overload is associated with hepatic oxidative damage to DNA in nonalcoholic steatohepatitis. Cancer Epidemiol. Biomarkers Prev. 18, 424–432 (2009).
112. Handa, P. et al. Iron overload results in hepatic oxidative stress, immune cell activation, and hepatocellular ballooning injury, leading to nonalcoholic steatohepatitis in genetically obese mice. Am. J. Physiol. Gastrointest. Liver Physiol. 310, G117–G127 (2016).
113. Tomita, K. et al. Tumour necrosis factor α signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice. Gut 55, 415–424 (2006).
114. Carter-Kent, C., Zein, N. N. & Feldstein, A. E. Cytokines in the pathogenesis of fatty liver and disease progression to steatohepatitis: implications for treatment. Am. J. Gastroenterol. 103, 1036–1042 (2008).
115. De Taeye, B. M. et al. Macrophage TNF-α contributes to insulin resistance and hepatic steatosis in diet-induced obesity. Am. J. Physiol. Endocrinol. Metab. 293, E713–E725 (2007).
116. Kodama, Y. et al. c-Jun N-terminal kinase-1 from hematopoietic cells mediates progression from hepatic steatosis to steatohepatitis and fibrosis in mice. Gastroenterology 137, 1467–1477 (2009).
117. Dixon, L. J., Berk, M., Thapaliya, S., Papouchado, B. G. & Feldstein, A. E. Caspase-1-mediated regulation of fibrogenesis in diet-induced steatohepatitis. Lab. Invest. 92, 713–723 (2012).
118. Wree, A. et al. NLRP3 inflammasome activation is required for fibrosis development in NAFLD. J. Mol. Med. 92, 1069–1082 (2014).
119. Pradere, J. P. 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, 1461–1473 (2013).
120. Negrin, K. A. et al. IL-1 signaling in obesity-induced hepatic lipogenesis and steatosis. PLOS ONE 9, e107265 (2014).
121. Tencerova, M. et al. Activated Kupffer cells inhibit insulin sensitivity in obese mice. FASEB J. 29, 2959–2969 (2015).
122. Mridha, A. R. et al. NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice. J. Hepatol. 66, 1037–1046 (2017).
123. Chen, L. et al. Selective depletion of hepatic Kupffer cells significantly alleviated hepatosteatosis and intrahepatic inflammation induced by high fat diet. Hepatogastroenterology 59, 1208–1212 (2012).
124. Gambino, R., Musso, G. & Cassader, M. Redox balance in the pathogenesis of nonalcoholic fatty liver disease: mechanisms and therapeutic opportunities. Antioxid. Redox Signal. 15, 1325–1365 (2011).
125. Malaguarnera, L. et al. Chitotriosidase gene expression in Kupffer cells from patients with non-alcoholic fatty liver disease. Gut 55, 1313–1320 (2006).
126. Bae, Y. S. et al. Macrophages generate reactive oxygen species in response to minimally oxidized low-density lipoprotein: toll-like receptor 4- and spleen tyrosine kinase-dependent activation of NADPH oxidase 2. Circ. Res. 104, 210–218 (2009).
127. Meng, T. et al. Propofol reduces lipopolysaccharide-induced, NADPH oxidase (NOX 2) mediated TNF-α and IL-6 production in macrophages. Clin. Dev. Immunol. 2013, 325481 (2013).
128. Asanuma, T. et al. Super paramagnetic iron oxide MRI shows defective Kupffer cell uptake function in non-alcoholic fatty liver disease. Gut 59, 258–266 (2010).
129. Cheong, H. et al. Phagocytic function of Kupffer cells in mouse nonalcoholic fatty liver disease models: evaluation with superparamagnetic iron oxide. J. Magn. Reson. Imaging 41, 1218–1227 (2015).
130. Tonan, T. et al. CD14 expression and Kupffer cell dysfunction in non-alcoholic steatohepatitis: superparamagnetic iron oxide-magnetic resonance image and pathologic correlation. J. Gastroenterol. Hepatol. 27, 789–796 (2012).
131. Schaffler, A., Scholmerich, J. & Buchler, C. Mechanisms of disease: adipocytokines and visceral adipose tissue — emerging role in nonalcoholic fatty liver disease. Nat. Clin. Pract. Gastroenterol. Hepatol. 2, 273–280 (2005).
132. Asghar, A. & Sheikh, N. Role of immune cells in obesity induced low grade inflammation and insulin resistance. Cell. Immunol. 315, 18–26 (2017).
133. Fuentes, L., Roszer, T. & Ricote, M. Inflammatory mediators and insulin resistance in obesity: role of nuclear receptor signaling in macrophages. Mediators Inflamm. 2010, 219583 (2010).
134. Bugianesi, E. et al. Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms. Diabetologia 48, 634–642 (2005).
135. Stanton, M. C. et al. Inflammatory signals shift from adipose to liver during high fat feeding and influence the development of steatohepatitis in mice. J. Inflamm. 8, 8 (2011).
136. Bijnen, M. et al. Adipose tissue macrophages induce hepatic neutrophil recruitment and macrophage accumulation in mice. Gut 67, 1317–1327 (2018). This comprehensive study demonstrates that adipose tissue macrophages contribute to increased hepatic neutrophil and macrophage infiltration and worsening liver damage, emphasizing the role of adipose tissue–liver crosstalk in obesity and NAFLD.
137. du Plessis, J. et al. Association of adipose tissue inflammation with histologic severity of nonalcoholic fatty liver disease. Gastroenterology 149, 635–648 (2015).
138. Cancello, R. et al. Increased infiltration of macrophages in omental adipose tissue is associated with marked hepatic lesions in morbid human obesity. Diabetes 55, 1554–1561 (2006).
139. Tordjman, J. et al. Structural and inflammatory heterogeneity in subcutaneous adipose tissue: relation with liver histopathology in morbid obesity. J. Hepatol. 56, 1152–1158 (2012).
140. Tordjman, J. et al. Association between omental adipose tissue macrophages and liver histopathology in morbid obesity: influence of glycemic status. J. Hepatol. 51, 354–362 (2009).
141. Polyzos, S. A., Kountouras, J. & Mantzoros, C. S. Leptin in nonalcoholic fatty liver disease: a narrative review. Metabolism 64, 60–78 (2015).
142. Gatselis, N. K., Ntaios, G., Makaritsis, K. & Dalekos, G. N. Adiponectin: a key playmaker adipocytokine in non-alcoholic fatty liver disease. Clin. Exp. Med. 14, 121–131 (2014).
143. Metlakunta, A. et al. Kupffer cells facilitate the acute effects of leptin on hepatic lipid metabolism. Am. J. Physiol. Endocrinol. Metab. 312, E11–E18 (2017).
144. Chatterjee, S. et al. Leptin is key to peroxynitrite-mediated oxidative stress and Kupffer cell activation in experimental non-alcoholic steatohepatitis. J. Hepatol. 58, 778–784 (2013). This mouse study suggests that leptin activates Kupffer cells in NASH.
145. Shen, J., Sakaida, I., Uchida, K., Terai, S. & Okita, K. Leptin enhances TNF-α production via p38 and JNK MAPK in LPS-stimulated Kupffer cells. Life Sci. 77, 1502–1515 (2005).
146. Imajo, K. et al. Hyperresponsivity to low-dose endotoxin during progression to nonalcoholic steatohepatitis is regulated by leptin-mediated signaling. Cell Metab. 16, 44–54 (2012).
147. Ikejima, K. et al. Leptin receptor-mediated signaling regulates hepatic fibrogenesis and remodeling of extracellular matrix in the rat. Gastroenterology 122, 1399–1410 (2002).
148. Wang, J. et al. Kupffer cells mediate leptin-induced liver fibrosis. Gastroenterology 137, 713–723 (2009).
149. De Minicis, S. et al. Reduced nicotinamide adenine dinucleotide phosphate oxidase mediates fibrotic and inflammatory effects of leptin on hepatic stellate cells. Hepatology 48, 2016–2026 (2008).
150. Saxena, N. K., Ikeda, K., Rockey, D. C., Friedman, S. L. & Anania, F. A. Leptin in hepatic fibrosis: evidence for increased collagen production in stellate cells and lean littermates of ob/ob mice. Hepatology 35, 762–771 (2002).
151. Huang, H., Park, P. H., McMullen, M. R. & Nagy, L. E. Mechanisms for the anti-inflammatory effects of adiponectin in macrophages. J. Gastroenterol. Hepatol. 23, S50–S53 (2008).
152. Tsatsanis, C. et al. Adiponectin induces TNF-α and IL-6 in macrophages and promotes tolerance to itself and other pro-inflammatory stimuli. Biochem. Biophys. Res. Commun. 335, 1254–1263 (2005).
153. Fukushima, J. et al. Adiponectin prevents progression of steatohepatitis in mice by regulating oxidative stress and Kupffer cell phenotype polarization. Hepatol. Res. 39, 724–738 (2009). This study demonstrates that adiponectin shifts Kupffer cell polarization towards the anti-inflammatory phenotype, suggesting beneficial effects of adiponectin on macrophages.
154. Luo, N. et al. Enhanced adiponectin actions by overexpression of adiponectin receptor 1 in macrophages. Atherosclerosis 228, 124–135 (2013).
155. Robert, O. et al. Decreased expression of the glucocorticoid receptor-GILZ pathway in Kupffer cells promotes liver inflammation in obese mice. J. Hepatol. 64, 916–924 (2016).
156. Ho, M. K. & Springer, T. A. Mac-1 antigen: quantitative expression in macrophage populations and tissues, and immunofluorescent localization in spleen. J. Immunol. 128, 2281–2286 (1982).
157. Traber, P. G. & Zomer, E. Therapy of experimental NASH and fibrosis with galectin inhibitors. PLOS ONE 8, e83481 (2013).
158. Harrison, S. A. et al. Randomised clinical study: GR-MD-02, a galectin-3 inhibitor, versus placebo in patients having non-alcoholic steatohepatitis with advanced fibrosis. Aliment. Pharmacol. Ther. 44, 1183–1198 (2016). This phase I clinical trial suggests that targeting macrophages via galectin 3 shows promise as a treatment option for NASH.
159. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02421094 (2017).
160. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02462967 (2018).
161. Lefebvre, E. et al. Antifibrotic effects of the dual CCR2/CCR5 antagonist cenicriviroc in animal models of liver and kidney fibrosis. PLOS ONE 11, e0158156 (2016).
162. Friedman, S. L. et al. A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis. Hepatology 67, 1754–1767 (2018). This phase II trial of a CCR2–CCR5 inhibitor suppressing monocyte recruitment demonstrates fibrosis improvement in patients with NASH.
163. Marra, F. & Tacke, F. Roles for chemokines in liver disease. Gastroenterology 147, 577–594 (2014).
164. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03028740 (2018).
165. Neuschwander-Tetri, B. A. et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 385, 956–965 (2015).
166. Yao, J. et al. FXR agonist GW4064 alleviates endotoxin-induced hepatic inflammation by repressing macrophage activation. World J. Gastroenterol. 20, 14430–14441 (2014).
167. McMahan, R. H. et al. Bile acid receptor activation modulates hepatic monocyte activity and improves nonalcoholic fatty liver disease. J. Biol. Chem. 288, 11761–11770 (2013).
168. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02548351 (2018).
169. Eguchi, Y. et al. Pilot study of liraglutide effects in non-alcoholic steatohepatitis and non-alcoholic fatty liver disease with glucose intolerance in Japanese patients (LEAN-J). Hepatol. Res. 45, 269–278 (2015).
170. Wang, X. C., Gusdon, A. M., Liu, H. & Qu, S. Effects of glucagon-like peptide-1 receptor agonists on non-alcoholic fatty liver disease and inflammation. World J. Gastroenterol. 20, 14821–14830 (2014).
171. Armstrong, M. J. et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 387, 679–690 (2016).
172. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02970942 (2018).
173. Wang, Y. et al. Exendin-4 decreases liver inflammation and atherosclerosis development simultaneously by reducing macrophage infiltration. Br. J. Pharmacol. 171, 723–734 (2014).
174. Yamamoto, T. et al. Glucagon-like peptide-1 analogue prevents nonalcoholic steatohepatitis in non-obese mice. World J. Gastroenterol. 22, 2512–2523 (2016).
175. Feng, X. et al. Chrysin attenuates inflammation by regulating M1/M2 status via activating PPARγ. Biochem. Pharmacol. 89, 503–514 (2014).
176. Luo, W., Xu, Q., Wang, Q., Wu, H. & Hua, J. Effect of modulation of PPAR-γ activity on Kupffer cells M1/M2 polarization in the development of non-alcoholic fatty liver disease. Sci. Rep. 7, 44612 (2017).
177. Odegaard, J. I. et al. Macrophage-specific PPARγ controls alternative activation and improves insulin resistance. Nature 447, 1116–1120 (2007).
178. Boettcher, E., Csako, G., Pucino, F., Wesley, R. & Loomba, R. Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis. Aliment. Pharmacol. Ther. 35, 66–75 (2012).
179. Cusi, K. et al. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial. Ann. Intern. Med. 165, 305–315 (2016).
180. He, S. et al. Pioglitazone prescription increases risk of bladder cancer in patients with type 2 diabetes: an updated meta-analysis. Tumour Biol. 35, 2095–2102 (2014).
181. Staels, B. et al. Hepatoprotective effects of the dual peroxisome proliferator-activated receptor α/δ agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology 58, 1941–1952 (2013).
182. Ratziu, V. et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology 150, 1147–1159 (2016).
183. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02704403 (2018).
184. Zeng, T., Zhang, C. L., Zhao, X. L. & Xie, K. Q. Pentoxifylline for the treatment of nonalcoholic fatty liver disease: a meta-analysis of randomized double-blind, placebo-controlled studies. Eur. J. Gastroenterol. Hepatol. 26, 646–653 (2014).
185. Loomba, R. et al. The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: a randomized, phase 2 trial. Hepatology 67, 549–559 (2017).
186. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03053063 (2018).
187. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03053050 (2018).
188. Handberg, A. et al. Plasma sCD36 is associated with markers of atherosclerosis, insulin resistance and fatty liver in a nondiabetic healthy population. J. Intern. Med. 271, 294–304 (2012).
189. Ogawa, Y. et al. Soluble CD14 levels reflect liver inflammation in patients with nonalcoholic steatohepatitis. PLOS ONE 8, e65211 (2013).
190. Holland-Fischer, P. et al. Kupffer cells are activated in cirrhotic portal hypertension and not normalised by TIPS. Gut 60, 1389–1393 (2011).
191. Kazankov, K. et al. Soluble CD163, a macrophage activation marker, is independently associated with fibrosis in patients with chronic viral hepatitis B and C. Hepatology 60, 521–530 (2014).
192. Sandahl, T. D. et al. Hepatic macrophage activation and the LPS pathway in patients with alcoholic hepatitis: a prospective cohort study. Am. J. Gastroenterol. 109, 1749–1756 (2014).
193. Gronbaek, H. et al. Macrophage activation markers predict mortality in patients with liver cirrhosis without or with acute-on-chronic liver failure (ACLF). J. Hepatol. 64, 813–822 (2016).
194. Kazankov, K. et al. The macrophage activation marker sCD163 is associated with changes in NAFLD and metabolic profile during lifestyle intervention in obese children. Pediatr. Obes. 10, 226–233 (2015).
195. Kazankov, K. et al. The macrophage activation marker sCD163 is associated with morphological disease stages in patients with non-alcoholic fatty liver disease. Liver Int. 36, 1549–1557 (2016). This study suggests that the specific macrophage marker soluble CD163 might be a good biomarker for the severity of NAFLD.
196. Mueller, J. L. et al. Circulating soluble CD163 is associated with steatohepatitis and advanced fibrosis in nonalcoholic fatty liver disease. Clin. Transl Gastroenterol. 6, e114 (2015).
197. Kazankov, K. et al. Macrophage activation marker soluble CD163 and non-alcoholic fatty liver disease in morbidly obese patients undergoing bariatric surgery. J. Gastroenterol. Hepatol. 30, 1293–1300 (2015).
198. Moller, H. J., Frikke-Schmidt, R., Moestrup, S. K., Nordestgaard, B. G. & Tybjaerg-Hansen, A. Serum soluble CD163 predicts risk of type 2 diabetes in the general population. Clin. Chem. 57, 291–297 (2011).
199. Kornek, M. et al. Circulating microparticles as disease-specific biomarkers of severity of inflammation in patients with hepatitis C or nonalcoholic steatohepatitis. Gastroenterology 143, 448–458 (2012).
200. Chalasani, N. et al. The diagnosis and management of NAFLD: practice guidance from the American Association for the Study of Liver Diseases. Hepatology 67, 328–357 (2018). This is the latest clinical practice guideline for nonalcoholic fatty liver disease from the American Association for the Study of Liver Diseases.