Subscribe to RSS
DOI: 10.1055/s-0039-1687851
Macrophages as Key Players during Adipose Tissue–Liver Crosstalk in Nonalcoholic Fatty Liver Disease
Publication History
Publication Date:
30 April 2019 (online)
![](https://www.thieme-connect.de/media/sld/201903/lookinside/thumbnails/10-1055-s-0039-1687851_1800100-1.jpg)
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in Western countries that could lead to serious health problems including liver failure, cancer, or death. The term NAFLD includes a spectrum of disease states with histological features ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). A key aspect within this research field is the identification of pathogenic factors that trigger inflammation, thus fueling the transition from nonalcoholic fatty liver to NASH. These inflammatory triggers may originate from within the liver as a result of innate immune cell activation and/or hepatocyte injury. Additionally, they may originate from other sites such as adipose tissue or the intestinal tract. In the current review, the authors will primarily focus on events within adipose tissue which may be of importance in triggering the disease progression. They specifically focus on the role of adipose tissue macrophages during NAFLD pathogenesis and how microenvironmental factors may shape their metabolic profile. They further dissect how redirecting the macrophage's metabolic profile alters their immunological functions. Finally, they discuss the opportunities and challenges of targeting macrophages to interfere in disease progression.
-
References
- 1 Younossi Z, Henry L. Contribution of alcoholic and nonalcoholic fatty liver disease to the burden of liver-related morbidity and mortality. Gastroenterology 2016; 150 (08) 1778-1785
- 2 Lallukka S, Yki-Järvinen H. Non-alcoholic fatty liver disease and risk of type 2 diabetes. Best Pract Res Clin Endocrinol Metab 2016; 30 (03) 385-395
- 3 Wong RJ, Aguilar M, Cheung R. , et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology 2015; 148 (03) 547-555
- 4 Rinella ME, Sanyal AJ. Management of NAFLD: a stage-based approach. Nat Rev Gastroenterol Hepatol 2016; 13 (04) 196-205
- 5 Adams LA, Anstee QM, Tilg H, Targher G. Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases. Gut 2017; 66 (06) 1138-1153
- 6 Musso G, Cassader M, Gambino R. Non-alcoholic steatohepatitis: emerging molecular targets and therapeutic strategies. Nat Rev Drug Discov 2016; 15 (04) 249-274
- 7 Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 2010; 52 (05) 1836-1846
- 8 Marra F, Svegliati-Baroni G. Lipotoxicity and the gut-liver axis in NASH pathogenesis. J Hepatol 2018; 68 (02) 280-295
- 9 Tremaroli V, Bäckhed F. Functional interactions between the gut microbiota and host metabolism. Nature 2012; 489 (7415): 242-249
- 10 Cai J, Zhang X-J, Li H. Role of innate immune signaling in non-alcoholic fatty liver disease. Trends Endocrinol Metab 2018; 29 (10) 712-722
- 11 Fuchs M, Schnabl B. Editors' introduction to the NAFLD and NASH special issue. Dig Dis Sci 2016; 61 (05) 1211-1213
- 12 Arrese M, Cabrera D, Kalergis AM, Feldstein AE. Innate immunity and inflammation in NAFLD/NASH. Dig Dis Sci 2016; 61 (05) 1294-1303
- 13 Chawla A, Nguyen KD, Goh YPS. Macrophage-mediated inflammation in metabolic disease. Nat Rev Immunol 2011; 11 (11) 738-749
- 14 Boutens L, Stienstra R. Adipose tissue macrophages: going off track during obesity. Diabetologia 2016; 59 (05) 879-894
- 15 Mulder P, Morrison MC, Wielinga PY, van Duyvenvoorde W, Kooistra T, Kleemann R. Surgical removal of inflamed epididymal white adipose tissue attenuates the development of non-alcoholic steatohepatitis in obesity. Int J Obes 2016; 40 (04) 675-684
- 16 Patsouris D, Li P-P, Thapar D, Chapman J, Olefsky JM, Neels JG. Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals. Cell Metab 2008; 8 (04) 301-309
- 17 Mulder P, Morrison MC, Verschuren L. , et al. Reduction of obesity-associated white adipose tissue inflammation by rosiglitazone is associated with reduced non-alcoholic fatty liver disease in LDLr-deficient mice. Sci Rep 2016; 6 (01) 31542
- 18 du Plessis J, van Pelt J, Korf H. , et al. Association of adipose tissue inflammation with histologic severity of nonalcoholic fatty liver disease. Gastroenterology 2015; 149 (03) 635.e14-648.e14
- 19 Wentworth JM, Naselli G, Brown WA. , et al. Pro-inflammatory CD11c+CD206+ adipose tissue macrophages are associated with insulin resistance in human obesity. Diabetes 2010; 59 (07) 1648-1656
- 20 Stanton MC, Chen S-C, Jackson JV. , et al. Inflammatory signals shift from adipose to liver during high fat feeding and influence the development of steatohepatitis in mice. J Inflamm (Lond) 2011; 8 (01) 8
- 21 Sun S, Ji Y, Kersten S, Qi L. Mechanisms of inflammatory responses in obese adipose tissue. Annu Rev Nutr 2012; 32 (01) 261-286
- 22 Cildir G, Akıncılar SC, Tergaonkar V. Chronic adipose tissue inflammation: all immune cells on the stage. Trends Mol Med 2013; 19 (08) 487-500
- 23 Ouchi N, Parker JL, Lugus JJ, Walsh K. Adipokines in inflammation and metabolic disease. Nat Rev Immunol 2011; 11 (02) 85-97
- 24 Gericke M, Weyer U, Braune J, Bechmann I, Eilers J. A method for long-term live imaging of tissue macrophages in adipose tissue explants. Am J Physiol Endocrinol Metab 2015; 308 (11) E1023-E1033
- 25 Lumeng CN, Deyoung SM, Bodzin JL, Saltiel AR. Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity. Diabetes 2007; 56 (01) 16-23
- 26 Lumeng CN, DelProposto JB, Westcott DJ, Saltiel AR. Phenotypic switching of adipose tissue macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes. Diabetes 2008; 57 (12) 3239-3246
- 27 Pétrilli V, Dostert C, Muruve DA, Tschopp J. The inflammasome: a danger sensing complex triggering innate immunity. Curr Opin Immunol 2007; 19 (06) 615-622
- 28 Vandanmagsar B, Youm Y-H, Ravussin A. , et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med 2011; 17 (02) 179-188
- 29 Wree A, Marra F. The inflammasome in liver disease. J Hepatol 2016; 65 (05) 1055-1056
- 30 Fassl SK, Austermann J, Papantonopoulou O. , et al. Transcriptome assessment reveals a dominant role for TLR4 in the activation of human monocytes by the alarmin MRP8. J Immunol 2015; 194 (02) 575-583
- 31 Xia C, Braunstein Z, Toomey AC, Zhong J, Rao X. S100 proteins as an important regulator of macrophage inflammation. Front Immunol 2018; 8: 1908
- 32 Zhang Y, Mei H, Chang X, Chen F, Zhu Y, Han X. Adipocyte-derived microvesicles from obese mice induce M1 macrophage phenotype through secreted miR-155. J Mol Cell Biol 2016; 8 (06) 505-517
- 33 Hundertmark J, Krenkel O, Tacke F. Adapted immune responses of myeloid-derived cells in fatty liver disease. Front Immunol 2018; 9: 2418
- 34 Bai Y, Sun Q. Macrophage recruitment in obese adipose tissue. Obes Rev 2015; 16 (02) 127-136
- 35 Kim D, Kim J, Yoon JH. , et al. CXCL12 secreted from adipose tissue recruits macrophages and induces insulin resistance in mice. Diabetologia 2014; 57 (07) 1456-1465
- 36 Kanda H, Tateya S, Tamori Y. , et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 2006; 116 (06) 1494-1505
- 37 Weisberg SP, Hunter D, Huber R. , et al. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest 2006; 116 (01) 115-124
- 38 Chung K-J, Chatzigeorgiou A, Economopoulou M. , et al. A self-sustained loop of inflammation-driven inhibition of beige adipogenesis in obesity. Nat Immunol 2017; 18 (06) 654-664
- 39 Ramkhelawon B, Hennessy EJ, Ménager M. , et al. Netrin-1 promotes adipose tissue macrophage retention and insulin resistance in obesity. Nat Med 2014; 20 (04) 377-384
- 40 Finucane OM, Reynolds CM, McGillicuddy FC. , et al. Macrophage migration inhibitory factor deficiency ameliorates high-fat diet induced insulin resistance in mice with reduced adipose inflammation and hepatic steatosis. PLoS One 2014; 9 (11) e113369
- 41 Finucane OM, Reynolds CM, McGillicuddy FC, Roche HM. Insights into the role of macrophage migration inhibitory factor in obesity and insulin resistance. Proc Nutr Soc 2012; 71 (04) 622-633
- 42 Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante Jr AW. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003; 112 (12) 1796-1808
- 43 Ginhoux F, Schultze JL, Murray PJ, Ochando J, Biswas SK. New insights into the multidimensional concept of macrophage ontogeny, activation and function. Nat Immunol 2016; 17 (01) 34-40
- 44 Ginhoux F, Jung S. Monocytes and macrophages: developmental pathways and tissue homeostasis. Nat Rev Immunol 2014; 14 (06) 392-404
- 45 Blander JM, Sander LE. Beyond pattern recognition: five immune checkpoints for scaling the microbial threat. Nat Rev Immunol 2012; 12 (03) 215-225
- 46 Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 2004; 25 (12) 677-686
- 47 Gordon S. Alternative activation of macrophages. Nat Rev Immunol 2003; 3 (01) 23-35
- 48 Odegaard JI, Ricardo-Gonzalez RR, Goforth MH. , et al. Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. Nature 2007; 447 (7148): 1116-1120
- 49 Spadaro O, Camell CD, Bosurgi L. , et al. IGF1 shapes macrophage activation in response to immunometabolic challenge. Cell Reports 2017; 19 (02) 225-234
- 50 Oh DY, Talukdar S, Bae EJ. , et al. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 2010; 142 (05) 687-698
- 51 Cho KW, Morris DL, Lumeng CN. Flow cytometry analyses of adipose tissue macrophages. Methods Enzymol 2014; 537: 297-314
- 52 Arkan MC, Hevener AL, Greten FR. , et al. IKK-β links inflammation to obesity-induced insulin resistance. Nat Med 2005; 11 (02) 191-198
- 53 Han MS, Jung DY, Morel C. , et al. JNK expression by macrophages promotes obesity-induced insulin resistance and inflammation. Science 2013; 339 (6116): 218-222
- 54 Xu X, Grijalva A, Skowronski A, van Eijk M, Serlie MJ, Ferrante Jr AW. Obesity activates a program of lysosomal-dependent lipid metabolism in adipose tissue macrophages independently of classic activation. Cell Metab 2013; 18 (06) 816-830
- 55 Kratz M, Coats BR, Hisert KB. , et al. Metabolic dysfunction drives a mechanistically distinct proinflammatory phenotype in adipose tissue macrophages. Cell Metab 2014; 20 (04) 614-625
- 56 Coats BR, Schoenfelt KQ, Barbosa-Lorenzi VC. , et al. Metabolically activated adipose tissue macrophages perform detrimental and beneficial functions during diet-induced obesity. Cell Reports 2017; 20 (13) 3149-3161
- 57 Serbulea V, Upchurch CM, Schappe MS. , et al. Macrophage phenotype and bioenergetics are controlled by oxidized phospholipids identified in lean and obese adipose tissue. Proc Natl Acad Sci U S A 2018; 115 (27) E6254-E6263
- 58 O'Neill LAJ, Pearce EJ. Immunometabolism governs dendritic cell and macrophage function. J Exp Med 2016; 213 (01) 15-23
- 59 Geeraerts X, Bolli E, Fendt S-M, Van Ginderachter JA. Macrophage metabolism as therapeutic target for cancer, atherosclerosis, and obesity. Front Immunol 2017; 8: 289
- 60 Chawla A. Control of macrophage activation and function by PPARs. Circ Res 2010; 106 (10) 1559-1569
- 61 Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 2007; 117 (01) 175-184
- 62 Huang SC-C, Smith AM, Everts B. , et al. Metabolic reprogramming mediated by the mTORC2-IRF4 signaling axis is essential for macrophage alternative activation. Immunity 2016; 45 (04) 817-830
- 63 Kelly B, O'Neill LA. Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res 2015; 25 (07) 771-784
- 64 Jha AK, Huang SCC, Sergushichev A. , et al. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity 2015; 42 (03) 419-430
- 65 Tannahill GM, Curtis AM, Adamik J. , et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature 2013; 496 (7444): 238-242
- 66 Remmerie A, Scott CL. Macrophages and lipid metabolism. Cell Immunol 2018; 330: 27-42
- 67 Tacke F. Targeting hepatic macrophages to treat liver diseases. J Hepatol 2017; 66 (06) 1300-1312
- 68 Friedman SL, Ratziu V, Harrison SA. , et al. A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis. Hepatology 2018; 67 (05) 1754-1767
- 69 Lefebvre E, Moyle G, Reshef R. , et al. Antifibrotic effects of the dual CCR2/CCR5 antagonist cenicriviroc in animal models of liver and kidney fibrosis. PLoS One 2016; 11 (06) e0158156
- 70 Krenkel O, Puengel T, Govaere O. , et al. Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis. Hepatology 2018; 67 (04) 1270-1283
- 71 Jain MR, Giri SR, Bhoi B. , et al. Dual PPARα/γ agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models. Liver Int 2018; 38 (06) 1084-1094
- 72 Ratziu V, Harrison SA, Francque S. , et al; GOLDEN-505 Investigator Study Group. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology 2016; 150 (05) 1147.e5-1159.e5
- 73 Shan B, Wang X, Wu Y. , et al. The metabolic ER stress sensor IRE1α suppresses alternative activation of macrophages and impairs energy expenditure in obesity. Nat Immunol 2017; 18 (05) 519-529
- 74 McMahan RH, Wang XX, Cheng LL. , et al. Bile acid receptor activation modulates hepatic monocyte activity and improves nonalcoholic fatty liver disease. J Biol Chem 2013; 288 (17) 11761-11770
- 75 Neuschwander-Tetri BA, Loomba R, Sanyal AJ. , et al; NASH Clinical Research Network. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 2015; 385 (9972): 956-965
- 76 Lin C-W, Zhang H, Li M. , et al. Pharmacological promotion of autophagy alleviates steatosis and injury in alcoholic and non-alcoholic fatty liver conditions in mice. J Hepatol 2013; 58 (05) 993-999
- 77 Xu J, Chi F, Guo T. , et al. NOTCH reprograms mitochondrial metabolism for proinflammatory macrophage activation. J Clin Invest 2015; 125 (04) 1579-1590
- 78 Haschemi A, Kosma P, Gille L. , et al. The sedoheptulose kinase CARKL directs macrophage polarization through control of glucose metabolism. Cell Metab 2012; 15 (06) 813-826
- 79 Sag D, Carling D, Stout RD, Suttles J. Adenosine 5′-monophosphate-activated protein kinase promotes macrophage polarization to an anti-inflammatory functional phenotype. J Immunol 2008; 181 (12) 8633-8641
- 80 Netea MG, van der Meer JWM. Trained immunity: an ancient way of remembering. Cell Host Microbe 2017; 21 (03) 297-300
- 81 Baardman J, Licht I, de Winther MPJ, Van den Bossche J. Metabolic-epigenetic crosstalk in macrophage activation. Epigenomics 2015; 7 (07) 1155-1164
- 82 Netea MG, Latz E, Mills KHG, O'Neill LAJ. Innate immune memory: a paradigm shift in understanding host defense. Nat Immunol 2015; 16 (07) 675-679
- 83 Cheng S-C, Quintin J, Cramer RA. , et al. mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity. Science 2014; 345 (6204): 1250684
- 84 Liu TF, Yoza BK, El Gazzar M, Vachharajani VT, McCall CE. NAD+-dependent SIRT1 deacetylase participates in epigenetic reprogramming during endotoxin tolerance. J Biol Chem 2011; 286 (11) 9856-9864
- 85 Liu TF, Vachharajani VT, Yoza BK, McCall CE. NAD+-dependent sirtuin 1 and 6 proteins coordinate a switch from glucose to fatty acid oxidation during the acute inflammatory response. J Biol Chem 2012; 287 (31) 25758-25769
- 86 Vachharajani VT, Liu T, Brown CM. , et al. SIRT1 inhibition during the hypoinflammatory phenotype of sepsis enhances immunity and improves outcome. J Leukoc Biol 2014; 96 (05) 785-796
- 87 Weavers H, Evans IR, Martin P, Wood W. Corpse engulfment generates a molecular memory that primes the macrophage inflammatory response. Cell 2016; 165 (07) 1658-1671
- 88 Bekkering S, Quintin J, Joosten LAB, van der Meer JWM, Netea MG, Riksen NP. Oxidized low-density lipoprotein induces long-term proinflammatory cytokine production and foam cell formation via epigenetic reprogramming of monocytes. Arterioscler Thromb Vasc Biol 2014; 34 (08) 1731-1738
- 89 Tripathi A, Debelius J, Brenner DA. , et al. The gut-liver axis and the intersection with the microbiome. Nat Rev Gastroenterol Hepatol 2018; 15 (07) 397-411
- 90 Samuel VT, Shulman GI. Nonalcoholic fatty liver disease as a nexus of metabolic and hepatic diseases. Cell Metab 2018; 27 (01) 22-41
- 91 Passeri MJ, Cinaroglu A, Gao C, Sadler KC. Hepatic steatosis in response to acute alcohol exposure in zebrafish requires sterol regulatory element binding protein activation. Hepatology 2009; 49 (02) 443-452
- 92 Tang T, Sui Y, Lian M, Li Z, Hua J. Pro-inflammatory activated Kupffer cells by lipids induce hepatic NKT cells deficiency through activation-induced cell death. PLoS One 2013; 8 (12) e81949
- 93 Carthew RW, Sontheimer EJ. Origins and mechanisms of miRNAs and siRNAs. Cell 2009; 136 (04) 642-655
- 94 Thomou T, Mori MA, Dreyfuss JM. , et al. Adipose-derived circulating miRNAs regulate gene expression in other tissues. Nature 2017; 542 (7642): 450-455
- 95 Korf H, van der Merwe S. Adipose-derived exosomal MicroRNAs orchestrate gene regulation in the liver: is this the missing link in nonalcoholic fatty liver disease?. Hepatology 2017; 66 (05) 1689-1691
- 96 Ying W, Riopel M, Bandyopadhyay G. , et al. Adipose tissue macrophage-derived exosomal miRNAs can modulate in vivo and in vitro insulin sensitivity. Cell 2017; 171 (02) 372.e12-384.e12
- 97 Jiang X, Jiang L, Shan A. , et al. Targeting hepatic miR-221/222 for therapeutic intervention of nonalcoholic steatohepatitis in mice. EBioMedicine 2018; 37 (October): 307-321
- 98 Wang J, Leclercq I, Brymora JM. , et al. Kupffer cells mediate leptin-induced liver fibrosis. Gastroenterology 2009; 137 (02) 713-723
- 99 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 2005; 77 (13) 1502-1515
- 100 Chatterjee S, Ganini D, Tokar EJ. , et al. Leptin is key to peroxynitrite-mediated oxidative stress and Kupffer cell activation in experimental non-alcoholic steatohepatitis. J Hepatol 2013; 58 (04) 778-784
- 101 Imajo K, Fujita K, Yoneda M. , et al. Hyperresponsivity to low-dose endotoxin during progression to nonalcoholic steatohepatitis is regulated by leptin-mediated signaling. Cell Metab 2012; 16 (01) 44-54
- 102 Xu A, Wang Y, Keshaw H, Xu LY, Lam KSL, Cooper GJS. The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J Clin Invest 2003; 112 (01) 91-100
- 103 Nagareddy PR, Kraakman M, Masters SL. , et al. Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity. Cell Metab 2014; 19 (05) 821-835
- 104 Tomita K, Tamiya G, Ando S. , et al. Tumour necrosis factor alpha signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice. Gut 2006; 55 (03) 415-424
- 105 Bijnen M, Josefs T, Cuijpers I. , et al. Adipose tissue macrophages induce hepatic neutrophil recruitment and macrophage accumulation in mice. Gut 2018; 67 (07) 1317-1327
- 106 Kishore P, Li W, Tonelli J. , et al. Adipocyte-derived factors potentiate nutrient-induced production of plasminogen activator inhibitor-1 by macrophages. Sci Transl Med 2010; 2 (20) 20ra15
- 107 Halpern KB, Shenhav R, Massalha H. , et al. Paired-cell sequencing enables spatial gene expression mapping of liver endothelial cells. Nat Biotechnol 2018; 36 (10) 962-970
- 108 MacParland SA, Liu JC, Ma X-Z. , et al. Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations. Nat Commun 2018; 9 (01) 4383