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Metabolic influence on macrophage polarization and pathogenesis

  • Thapa, Bikash (Institute of Bioscience and Biotechnology, Hallym University) ;
  • Lee, Keunwook (Institute of Bioscience and Biotechnology, Hallym University)
  • Received : 2019.04.21
  • Published : 2019.06.30

Abstract

Macrophages play an essential role not only in mediating the first line of defense but also in maintaining tissue homeostasis. In response to extrinsic factors derived from a given tissue, macrophages activate different functional programs to produce polarized macrophage populations responsible for inducing inflammation against microbes, removing cellular debris, and tissue repair. However, accumulating evidence has revealed that macrophage polarization is pivotal in the pathophysiology of metabolic syndromes and cancer, as well as in infectious and autoimmune diseases. Recent advances in transcriptomic and metabolomic studies have highlighted the link between metabolic rewiring of macrophages and their functional plasticity. These findings imply that metabolic adaption to their surrounding microenvironment instructs activation of macrophages with functionally distinct phenotypes, which in turn probably leads to the pathogenesis of a wide spectrum of diseases. In this review, we have introduced emerging concepts in immunometabolism with focus on the impact on functional activation of macrophages. Furthermore, we have discussed the implication of macrophage plasticity on the pathogenesis of metabolic syndromes and cancer, and how the disease microenvironment manipulates macrophage metabolism with regard to the pathophysiology.

Keywords

References

  1. Cohn ZA and Benson B (1965) The Differentiation of Mononuclear Phagocytes. Morphology, Cytochemistry, and Biochemistry. J Exp Med 121, 153-170 https://doi.org/10.1084/jem.121.1.153
  2. Rouzer CA, Scott WA, Hamill AL, Liu FT, Katz DH and Cohn ZA (1982) Secretion of leukotriene C and other arachidonic acid metabolites by macrophages challenged with immunoglobulin E immune complexes. J Exp Med 156, 1077-1086 https://doi.org/10.1084/jem.156.4.1077
  3. Poltorak A, He X, Smirnova I et al (1998) Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282, 2085-2088 https://doi.org/10.1126/science.282.5396.2085
  4. Takeda K, Kaisho T and Akira S (2003) Toll-like receptors. Annu Rev Immunol 21, 335-376 https://doi.org/10.1146/annurev.immunol.21.120601.141126
  5. Medzhitov R, Preston-Hurlburt P and Janeway CA, Jr. (1997) A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388, 394-397 https://doi.org/10.1038/41131
  6. Witting A, Muller P, Herrmann A, Kettenmann H and Nolte C (2000) Phagocytic clearance of apoptotic neurons by Microglia/Brain macrophages in vitro: involvement of lectin-, integrin-, and phosphatidylserinemediated recognition. J Neurochem 75, 1060-1070 https://doi.org/10.1046/j.1471-4159.2000.0751060.x
  7. Teitelbaum SL (2000) Bone resorption by osteoclasts. Science 289, 1504-1508 https://doi.org/10.1126/science.289.5484.1504
  8. van Iwaarden JF, Claassen E, Jeurissen SH, Haagsman HP and Kraal G (2001) Alveolar macrophages, surfactant lipids, and surfactant protein B regulate the induction of immune responses via the airways. Am J Respir Cell Mol Biol 24, 452-458 https://doi.org/10.1165/ajrcmb.24.4.4239
  9. Willekens FL, Werre JM, Kruijt JK et al (2005) Liver Kupffer cells rapidly remove red blood cell-derived vesicles from the circulation by scavenger receptors. Blood 105, 2141-2145 https://doi.org/10.1182/blood-2004-04-1578
  10. Leibovich SJ and Ross R (1975) The role of the macrophage in wound repair. A study with hydrocortisone and antimacrophage serum. Am J Pathol 78, 71-100
  11. Polverini PJ, Cotran PS, Gimbrone MA Jr and Unanue ER (1977) Activated macrophages induce vascular proliferation. Nature 269, 804-806 https://doi.org/10.1038/269804a0
  12. Hunt TK, Knighton DR, Thakral KK, Goodson WH 3rd and Andrews WS (1984) Studies on inflammation and wound healing: angiogenesis and collagen synthesis stimulated in vivo by resident and activated wound macrophages. Surgery 96, 48-54
  13. Koh TJ and DiPietro LA (2011) Inflammation and wound healing: the role of the macrophage. Expert Rev Mol Med 13, e23 https://doi.org/10.1017/S1462399411001943
  14. Alliot F, Godin I and Pessac B (1999) Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain. Brain Res Dev Brain Res 117, 145-152 https://doi.org/10.1016/S0165-3806(99)00113-3
  15. Naito M, Hasegawa G and Takahashi K (1997) Development, differentiation, and maturation of Kupffer cells. Microsc Res Tech 39, 350-364 https://doi.org/10.1002/(SICI)1097-0029(19971115)39:4<350::AID-JEMT5>3.0.CO;2-L
  16. Guilliams M, De Kleer I, Henri S et al (2013) Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF. J Exp Med 210, 1977-1992 https://doi.org/10.1084/jem.20131199
  17. Ginhoux F and Guilliams M (2016) Tissue-Resident Macrophage Ontogeny and Homeostasis. Immunity 44, 439-449 https://doi.org/10.1016/j.immuni.2016.02.024
  18. Matute-Bello G, Lee JS, Frevert CW et al (2004) Optimal timing to repopulation of resident alveolar macrophages with donor cells following total body irradiation and bone marrow transplantation in mice. J Immunol Methods 292, 25-34 https://doi.org/10.1016/j.jim.2004.05.010
  19. Scott CL, Zheng F, De Baetselier P et al (2016) Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells. Nat Commun 7, 10321 https://doi.org/10.1038/ncomms10321
  20. Chang CH, Qiu J, O'Sullivan D et al (2015) Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression. Cell 162, 1229-1241 https://doi.org/10.1016/j.cell.2015.08.016
  21. Westendorf AM, Skibbe K, Adamczyk A et al (2017) Hypoxia Enhances Immunosuppression by Inhibiting CD4+ Effector T Cell Function and Promoting Treg Activity. Cell Physiol Biochem 41, 1271-1284 https://doi.org/10.1159/000464429
  22. Clambey ET, McNamee EN, Westrich JA et al (2012) Hypoxia-inducible factor-1 alpha-dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa. Proc Natl Acad Sci U S A 109, E2784-2793 https://doi.org/10.1073/pnas.1202366109
  23. Bantug GR, Galluzzi L, Kroemer G and Hess C (2018) The spectrum of T cell metabolism in health and disease. Nat Rev Immunol 18, 19-34 https://doi.org/10.1038/nri.2017.99
  24. Mackaness GB (1962) Cellular resistance to infection. J Exp Med 116, 381-406 https://doi.org/10.1084/jem.116.3.381
  25. Mosser DM and Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8, 958-969 https://doi.org/10.1038/nri2448
  26. Sica A and Mantovani A (2012) Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 122, 787-795 https://doi.org/10.1172/JCI59643
  27. Stein M, Keshav S, Harris N and Gordon S (1992) Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation. J Exp Med 176, 287-292 https://doi.org/10.1084/jem.176.1.287
  28. Gordon S and Martinez FO (2010) Alternative activation of macrophages: mechanism and functions. Immunity 32, 593-604 https://doi.org/10.1016/j.immuni.2010.05.007
  29. Wynn TA and Vannella KM (2016) Macrophages in Tissue Repair, Regeneration, and Fibrosis. Immunity 44, 450-462 https://doi.org/10.1016/j.immuni.2016.02.015
  30. Rath M, Muller I, Kropf P, Closs EI and Munder M (2014) Metabolism via Arginase or Nitric Oxide Synthase: Two Competing Arginine Pathways in Macrophages. Front Immunol 5, 532
  31. Mills CD, Kincaid K, Alt JM, Heilman MJ and Hill AM (2000) M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol 164, 6166-6173 https://doi.org/10.4049/jimmunol.164.12.6166
  32. Murray PJ, Allen JE, Biswas SK et al (2014) Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41, 14-20 https://doi.org/10.1016/j.immuni.2014.06.008
  33. Qian BZ and Pollard JW (2010) Macrophage diversity enhances tumor progression and metastasis. Cell 141, 39-51 https://doi.org/10.1016/j.cell.2010.03.014
  34. Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A and Locati M (2004) The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25, 677-686 https://doi.org/10.1016/j.it.2004.09.015
  35. Roszer T (2015) Understanding the Mysterious M2 Macrophage through Activation Markers and Effector Mechanisms. Mediators Inflamm 2015, 816460 https://doi.org/10.1155/2015/816460
  36. Pearce EL (2010) Metabolism in T cell activation and differentiation. Curr Opin Immunol 22, 314-320 https://doi.org/10.1016/j.coi.2010.01.018
  37. Buck MD, O'Sullivan D and Pearce EL (2015) T cell metabolism drives immunity. J Exp Med 212, 1345-1360 https://doi.org/10.1084/jem.20151159
  38. O'Sullivan D, van der Windt GJ, Huang SC et al (2014) Memory CD8(+) T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development. Immunity 41, 75-88 https://doi.org/10.1016/j.immuni.2014.06.005
  39. Slack M, Wang T and Wang R (2015) T cell metabolic reprogramming and plasticity. Mol Immunol 68, 507-512 https://doi.org/10.1016/j.molimm.2015.07.036
  40. Wang T, Liu H, Lian G, Zhang SY, Wang X and Jiang C (2017) HIF1alpha-Induced Glycolysis Metabolism Is Essential to the Activation of Inflammatory Macrophages. Mediators Inflamm 2017, 9029327 https://doi.org/10.1155/2017/9029327
  41. Freemerman AJ, Johnson AR, Sacks GN et al (2014) Metabolic reprogramming of macrophages: glucose transporter 1 (GLUT1)-mediated glucose metabolism drives a proinflammatory phenotype. J Biol Chem 289, 7884-7896 https://doi.org/10.1074/jbc.M113.522037
  42. Shirai T, Nazarewicz RR, Wallis BB et al (2016) The glycolytic enzyme PKM2 bridges metabolic and inflammatory dysfunction in coronary artery disease. J Exp Med 213, 337-354 https://doi.org/10.1084/jem.20150900
  43. Semba H, Takeda N, Isagawa T et al (2016) HIF-1alpha-PDK1 axis-induced active glycolysis plays an essential role in macrophage migratory capacity. Nat Commun 7, 11635 https://doi.org/10.1038/ncomms11635
  44. Geeraerts X, Bolli E, Fendt SM and Van Ginderachter JA (2017) Macrophage Metabolism As Therapeutic Target for Cancer, Atherosclerosis, and Obesity. Front Immunol 8, 289
  45. Ryan DG and O'Neill LAJ (2017) Krebs cycle rewired for macrophage and dendritic cell effector functions. FEBS Lett 591, 2992-3006 https://doi.org/10.1002/1873-3468.12744
  46. Williams NC and O'Neill LAJ (2018) A Role for the Krebs Cycle Intermediate Citrate in Metabolic Reprogramming in Innate Immunity and Inflammation. Front Immunol 9, 141 https://doi.org/10.3389/fimmu.2018.00141
  47. Infantino V, Convertini P, Cucci L et al (2011) The mitochondrial citrate carrier: a new player in inflammation. Biochem J 438, 433-436 https://doi.org/10.1042/BJ20111275
  48. Everts B, Amiel E, van der Windt GJ et al (2012) Commitment to glycolysis sustains survival of NO-producing inflammatory dendritic cells. Blood 120, 1422-1431 https://doi.org/10.1182/blood-2012-03-419747
  49. Van den Bossche J, Baardman J, Otto NA et al (2016) Mitochondrial Dysfunction Prevents Repolarization of Inflammatory Macrophages. Cell Rep 17, 684-696 https://doi.org/10.1016/j.celrep.2016.09.008
  50. Michelucci A, Cordes T, Ghelfi J et al (2013) Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production. Proc Natl Acad Sci U S A 110, 7820-7825 https://doi.org/10.1073/pnas.1218599110
  51. Cordes T, Wallace M, Michelucci A et al (2016) Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels. J Biol Chem 291, 14274-14284 https://doi.org/10.1074/jbc.M115.685792
  52. Lampropoulou V, Sergushichev A, Bambouskova M et al (2016) Itaconate Links Inhibition of Succinate Dehydrogenase with Macrophage Metabolic Remodeling and Regulation of Inflammation. Cell Metab 24, 158-166 https://doi.org/10.1016/j.cmet.2016.06.004
  53. Tannahill GM, Curtis AM, Adamik J et al (2013) Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha. Nature 496, 238-242 https://doi.org/10.1038/nature11986
  54. Eggleston LV and Krebs HA (1974) Regulation of the pentose phosphate cycle. Biochem J 138, 425-435 https://doi.org/10.1042/bj1380425
  55. Everts B, Amiel E, Huang SC et al (2014) TLR-driven early glycolytic reprogramming via the kinases TBK1-IKKvarepsilon supports the anabolic demands of dendritic cell activation. Nat Immunol 15, 323-332 https://doi.org/10.1038/ni.2833
  56. Koo SJ, Szczesny B, Wan X, Putluri N and Garg NJ (2018) Pentose Phosphate Shunt Modulates Reactive Oxygen Species and Nitric Oxide Production Controlling Trypanosoma cruzi in Macrophages. Front Immunol 9, 202 https://doi.org/10.3389/fimmu.2018.00202
  57. Haschemi A, Kosma P, Gille L et al (2012) The sedoheptulose kinase CARKL directs macrophage polarization through control of glucose metabolism. Cell Metab 15, 813-826 https://doi.org/10.1016/j.cmet.2012.04.023
  58. Baardman J, Verberk SGS, Prange KHM et al (2018) A Defective Pentose Phosphate Pathway Reduces Inflammatory Macrophage Responses during Hypercholesterolemia. Cell Rep 25, 2044-2052 e2045 https://doi.org/10.1016/j.celrep.2018.10.092
  59. Galvan-Pena S and O'Neill LA (2014) Metabolic reprograming in macrophage polarization. Front Immunol 5, 420
  60. Clementi E, Brown GC, Feelisch M and Moncada S (1998) Persistent inhibition of cell respiration by nitric oxide: crucial role of S-nitrosylation of mitochondrial complex I and protective action of glutathione. Proc Natl Acad Sci U S A 95, 7631-7636 https://doi.org/10.1073/pnas.95.13.7631
  61. Heming M, Gran S, Jauch SL et al (2018) Peroxisome Proliferator-Activated Receptor-gamma Modulates the Response of Macrophages to Lipopolysaccharide and Glucocorticoids. Front Immunol 9, 893 https://doi.org/10.3389/fimmu.2018.00893
  62. Lee JH, Phelan P, Shin M et al (2018) SREBP-1astimulated lipid synthesis is required for macrophage phagocytosis downstream of TLR4-directed mTORC1. Proc Natl Acad Sci U S A 115, E12228-E12234 https://doi.org/10.1073/pnas.1813458115
  63. Horton JD, Goldstein JL and Brown MS (2002) SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 109, 1125-1131 https://doi.org/10.1172/JCI0215593
  64. Im SS, Yousef L, Blaschitz C et al (2011) Linking lipid metabolism to the innate immune response in macrophages through sterol regulatory element binding protein-1a. Cell Metab 13, 540-549 https://doi.org/10.1016/j.cmet.2011.04.001
  65. Schneider JG, Yang Z, Chakravarthy MV et al (2010) Macrophage fatty-acid synthase deficiency decreases diet-induced atherosclerosis. J Biol Chem 285, 23398-23409 https://doi.org/10.1074/jbc.M110.100321
  66. Vats D, Mukundan L, Odegaard JI et al (2006) Oxidative metabolism and PGC-1beta attenuate macrophagemediated inflammation. Cell Metab 4, 13-24 https://doi.org/10.1016/j.cmet.2006.05.011
  67. Huang SC, Everts B, Ivanova Y et al (2014) Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages. Nat Immunol 15, 846-855 https://doi.org/10.1038/ni.2956
  68. Malandrino MI, Fucho R, Weber M et al (2015) Enhanced fatty acid oxidation in adipocytes and macrophages reduces lipid-induced triglyceride accumulation and inflammation. Am J Physiol Endocrinol Metab 308, E756-769 https://doi.org/10.1152/ajpendo.00362.2014
  69. Nomura M, Liu J, Rovira II et al (2016) Fatty acid oxidation in macrophage polarization. Nat Immunol 17, 216-217 https://doi.org/10.1038/ni.3366
  70. Namgaladze D and Brune B (2014) Fatty acid oxidation is dispensable for human macrophage IL-4-induced polarization. Biochim Biophys Acta 1841, 1329-1335 https://doi.org/10.1016/j.bbalip.2014.06.007
  71. Huang SC, Smith AM, Everts B et al (2016) Metabolic Reprogramming Mediated by the mTORC2-IRF4 Signaling Axis Is Essential for Macrophage Alternative Activation. Immunity 45, 817-830 https://doi.org/10.1016/j.immuni.2016.09.016
  72. Covarrubias AJ, Aksoylar HI, Yu J et al (2016) Akt-mTORC1 signaling regulates Acly to integrate metabolic input to control of macrophage activation. Elife 5, e11612 https://doi.org/10.7554/eLife.11612
  73. Wang F, Zhang S, Vuckovic I et al (2018) Glycolytic Stimulation Is Not a Requirement for M2 Macrophage Differentiation. Cell Metab 28, 463-475 e464 https://doi.org/10.1016/j.cmet.2018.08.012
  74. Yang C, Ko B, Hensley CT et al (2014) Glutamine oxidation maintains the TCA cycle and cell survival during impaired mitochondrial pyruvate transport. Mol Cell 56, 414-424 https://doi.org/10.1016/j.molcel.2014.09.025
  75. Wise DR and Thompson CB (2010) Glutamine addiction: a new therapeutic target in cancer. Trends Biochem Sci 35, 427-433 https://doi.org/10.1016/j.tibs.2010.05.003
  76. Ligthart-Melis GC, van de Poll MC, Boelens PG, Dejong CH, Deutz NE and van Leeuwen PA (2008) Glutamine is an important precursor for de novo synthesis of arginine in humans. Am J Clin Nutr 87, 1282-1289 https://doi.org/10.1093/ajcn/87.5.1282
  77. Palmieri EM, Menga A, Martin-Perez R et al (2017) Pharmacologic or Genetic Targeting of Glutamine Synthetase Skews Macrophages toward an M1-like Phenotype and Inhibits Tumor Metastasis. Cell Rep 20, 1654-1666 https://doi.org/10.1016/j.celrep.2017.07.054
  78. Mori M and Gotoh T (2004) Arginine metabolic enzymes, nitric oxide and infection. J Nutr 134, 2820S-2825S; discussion 2853S https://doi.org/10.1093/jn/134.10.2820S
  79. Benoit M, Desnues B and Mege JL (2008) Macrophage polarization in bacterial infections. J Immunol 181, 3733-3739 https://doi.org/10.4049/jimmunol.181.6.3733
  80. Nardin A and Abastado JP (2008) Macrophages and cancer. Front Biosci 13, 3494-3505 https://doi.org/10.2741/2944
  81. Hotamisligil GS, Arner P, Caro JF, Atkinson RL and Spiegelman BM (1995) Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest 95, 2409-2415 https://doi.org/10.1172/JCI117936
  82. Schreyer SA, Chua SC, Jr. and LeBoeuf RC (1998) Obesity and diabetes in TNF-alpha receptor- deficient mice. J Clin Invest 102, 402-411 https://doi.org/10.1172/JCI2849
  83. Gonzalez-Gay MA, Gonzalez-Juanatey C, Vazquez-Rodriguez TR, Miranda-Filloy JA and Llorca J (2010) Insulin resistance in rheumatoid arthritis: the impact of the anti-TNF-alpha therapy. Ann N Y Acad Sci 1193, 153-159 https://doi.org/10.1111/j.1749-6632.2009.05287.x
  84. Lumeng CN, Bodzin JL and Saltiel AR (2007) Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 117, 175-184 https://doi.org/10.1172/JCI29881
  85. Pirzgalska RM and Domingos AI (2018) Macrophages in obesity. Cell Immunol 330, 183-187 https://doi.org/10.1016/j.cellimm.2018.04.014
  86. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL and Ferrante AW Jr (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112, 1796-1808 https://doi.org/10.1172/JCI200319246
  87. Frikke-Schmidt H, Zamarron BF, O'Rourke RW, Sandoval DA, Lumeng CN and Seeley RJ (2017) Weight loss independent changes in adipose tissue macrophage and T cell populations after sleeve gastrectomy in mice. Mol Metab 6, 317-326 https://doi.org/10.1016/j.molmet.2017.02.004
  88. Vandanmagsar B, Youm YH, Ravussin A et al (2011) The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med 17, 179-188 https://doi.org/10.1038/nm.2279
  89. Meier CA, Bobbioni E, Gabay C, Assimacopoulos-Jeannet F, Golay A and Dayer JM (2002) IL-1 receptor antagonist serum levels are increased in human obesity: a possible link to the resistance to leptin? J Clin Endocrinol Metab 87, 1184-1188 https://doi.org/10.1210/jcem.87.3.8351
  90. Spranger J, Kroke A, Mohlig M et al (2003) Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Diabetes 52, 812-817 https://doi.org/10.2337/diabetes.52.3.812
  91. Sauter NS, Schulthess FT, Galasso R, Castellani LW and Maedler K (2008) The antiinflammatory cytokine interleukin-1 receptor antagonist protects from high-fat diet-induced hyperglycemia. Endocrinology 149, 2208-2218 https://doi.org/10.1210/en.2007-1059
  92. Thomas D and Apovian C (2017) Macrophage functions in lean and obese adipose tissue. Metabolism 72, 120-143 https://doi.org/10.1016/j.metabol.2017.04.005
  93. Ricardo-Gonzalez RR, Red Eagle A, Odegaard JI et al (2010) IL-4/STAT6 immune axis regulates peripheral nutrient metabolism and insulin sensitivity. Proc Natl Acad Sci U S A 107, 22617-22622 https://doi.org/10.1073/pnas.1009152108
  94. Lesna IK, Cejkova S, Kralova A et al (2017) Human adipose tissue accumulation is associated with pro-inflammatory changes in subcutaneous rather than visceral adipose tissue. Nutr Diabetes 7, e264 https://doi.org/10.1038/nutd.2017.15
  95. Boutens L, Hooiveld GJ, Dhingra S, Cramer RA, Netea MG and Stienstra R (2018) Unique metabolic activation of adipose tissue macrophages in obesity promotes inflammatory responses. Diabetologia 61, 942-953 https://doi.org/10.1007/s00125-017-4526-6
  96. Johnson AR, Qin Y, Cozzo AJ et al (2016) Metabolic reprogramming through fatty acid transport protein 1 (FATP1) regulates macrophage inflammatory potential and adipose inflammation. Mol Metab 5, 506-526 https://doi.org/10.1016/j.molmet.2016.04.005
  97. Shapiro H, Pecht T, Shaco-Levy R et al (2013) Adipose tissue foam cells are present in human obesity. J Clin Endocrinol Metab 98, 1173-1181 https://doi.org/10.1210/jc.2012-2745
  98. Rogero MM and Calder PC (2018) Obesity, Inflammation, Toll-Like Receptor 4 and Fatty Acids. Nutrients 10, 432 https://doi.org/10.3390/nu10040432
  99. Xu X, Grijalva A, Skowronski A, van Eijk M, Serlie MJ and Ferrante AW Jr (2013) Obesity activates a program of lysosomal-dependent lipid metabolism in adipose tissue macrophages independently of classic activation. Cell Metab 18, 816-830 https://doi.org/10.1016/j.cmet.2013.11.001
  100. Hick RW, Gruver AL, Ventevogel MS, Haynes BF and Sempowski GD (2006) Leptin selectively augments thymopoiesis in leptin deficiency and lipopolysaccharideinduced thymic atrophy. J Immunol 177, 169-176 https://doi.org/10.4049/jimmunol.177.1.169
  101. Fernandez-Riejos P, Najib S, Santos-Alvarez J et al (2010) Role of leptin in the activation of immune cells. Mediators Inflamm 2010, 568343
  102. Sheng T and Yang K (2008) Adiponectin and its association with insulin resistance and type 2 diabetes. J Genet Genomics 35, 321-326 https://doi.org/10.1016/S1673-8527(08)60047-8
  103. Ajuwon KM and Spurlock ME (2005) Adiponectin inhibits LPS-induced NF-kappaB activation and IL-6 production and increases PPARgamma2 expression in adipocytes. Am J Physiol Regul Integr Comp Physiol 288, R1220-1225 https://doi.org/10.1152/ajpregu.00397.2004
  104. Ohashi K, Parker JL, Ouchi N et al (2010) Adiponectin promotes macrophage polarization toward an antiinflammatory phenotype. J Biol Chem 285, 6153-6160 https://doi.org/10.1074/jbc.M109.088708
  105. Tsatsanis C, Zacharioudaki V, Androulidaki A et al (2005) Adiponectin induces TNF-alpha and IL-6 in macrophages and promotes tolerance to itself and other pro-inflammatory stimuli. Biochem Biophys Res Commun 335, 1254-1263 https://doi.org/10.1016/j.bbrc.2005.07.197
  106. Moore KJ, Sheedy FJ and Fisher EA (2013) Macrophages in atherosclerosis: a dynamic balance. Nat Rev Immunol 13, 709-721 https://doi.org/10.1038/nri3520
  107. Chen W, Bural GG, Torigian DA, Rader DJ and Alavi A (2009) Emerging role of FDG-PET/CT in assessing atherosclerosis in large arteries. Eur J Nucl Med Mol Imaging 36, 144-151 https://doi.org/10.1007/s00259-008-0947-2
  108. Folco EJ, Sheikine Y, Rocha VZ et al (2011) Hypoxia but not inflammation augments glucose uptake in human macrophages: Implications for imaging atherosclerosis with 18fluorine-labeled 2-deoxy-D-glucose positron emission tomography. J Am Coll Cardiol 58, 603-614 https://doi.org/10.1016/j.jacc.2011.03.044
  109. Sarrazy V, Viaud M, Westerterp M et al (2016) Disruption of Glut1 in Hematopoietic Stem Cells Prevents Myelopoiesis and Enhanced Glucose Flux in Atheromatous Plaques of ApoE(-/-) Mice. Circ Res 118, 1062-1077 https://doi.org/10.1161/CIRCRESAHA.115.307599
  110. Chait A and Bornfeldt KE (2009) Diabetes and atherosclerosis: is there a role for hyperglycemia? J Lipid Res 50 Suppl, S335-339 https://doi.org/10.1194/jlr.R800059-JLR200
  111. Nagareddy PR, Murphy AJ, Stirzaker RA et al (2013) Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis. Cell Metab 17, 695-708 https://doi.org/10.1016/j.cmet.2013.04.001
  112. Terasaki M, Hiromura M, Mori Y et al (2015) Amelioration of Hyperglycemia with a Sodium-Glucose Cotransporter 2 Inhibitor Prevents Macrophage-Driven Atherosclerosis through Macrophage Foam Cell Formation Suppression in Type 1 and Type 2 Diabetic Mice. PLoS One 10, e0143396 https://doi.org/10.1371/journal.pone.0143396
  113. Nishizawa T, Kanter JE, Kramer F et al (2014) Testing the role of myeloid cell glucose flux in inflammation and atherosclerosis. Cell Rep 7, 356-365 https://doi.org/10.1016/j.celrep.2014.03.028
  114. Yang X, Li Y, Ren X et al (2017) Oxidative Stress-Mediated Atherosclerosis: Mechanisms and Therapies. Front Physiol 8, 600 https://doi.org/10.3389/fphys.2017.00600
  115. Wang Y, Wang GZ, Rabinovitch PS and Tabas I (2014) Macrophage mitochondrial oxidative stress promotes atherosclerosis and nuclear factor-kappaB-mediated inflammation in macrophages. Circ Res 114, 421-433 https://doi.org/10.1161/CIRCRESAHA.114.302153
  116. Cardilo-Reis L, Gruber S, Schreier SM et al (2012) Interleukin-13 protects from atherosclerosis and modulates plaque composition by skewing the macrophage phenotype. EMBO Mol Med 4, 1072-1086 https://doi.org/10.1002/emmm.201201374
  117. Wang Y, Wang W, Wang N, Tall AR and Tabas I (2017) Mitochondrial Oxidative Stress Promotes Atherosclerosis and Neutrophil Extracellular Traps in Aged Mice. Arterioscler Thromb Vasc Biol 37, e99-e107 https://doi.org/10.1161/ATVBAHA.117.309580
  118. Vink A, Schoneveld AH, Lamers D et al (2007) HIF-1 alpha expression is associated with an atheromatous inflammatory plaque phenotype and upregulated in activated macrophages. Atherosclerosis 195, e69-75 https://doi.org/10.1016/j.atherosclerosis.2007.05.026
  119. Aarup A, Pedersen TX, Junker N et al (2016) Hypoxia-Inducible Factor-1alpha Expression in Macrophages Promotes Development of Atherosclerosis. Arterioscler Thromb Vasc Biol 36, 1782-1790 https://doi.org/10.1161/ATVBAHA.116.307830
  120. Zhang QW, Liu L, Gong CY et al (2012) Prognostic significance of tumor-associated macrophages in solid tumor: a meta-analysis of the literature. PLoS One 7, e50946 https://doi.org/10.1371/journal.pone.0050946
  121. Argyle D and Kitamura T (2018) Targeting Macrophage-Recruiting Chemokines as a Novel Therapeutic Strategy to Prevent the Progression of Solid Tumors. Front Immunol 9, 2629 https://doi.org/10.3389/fimmu.2018.02629
  122. Chanmee T, Ontong P, Konno K and Itano N (2014) Tumor-associated macrophages as major players in the tumor microenvironment. Cancers (Basel) 6, 1670-1690 https://doi.org/10.3390/cancers6031670
  123. Lin EY, Nguyen AV, Russell RG and Pollard JW (2001) Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J Exp Med 193, 727-740 https://doi.org/10.1084/jem.193.6.727
  124. Quatromoni JG and Eruslanov E (2012) Tumor-associated macrophages: function, phenotype, and link to prognosis in human lung cancer. Am J Transl Res 4, 376-389
  125. Liberti MV and Locasale JW (2016) The Warburg Effect: How Does it Benefit Cancer Cells? Trends Biochem Sci 41, 211-218 https://doi.org/10.1016/j.tibs.2015.12.001
  126. Romero-Garcia S, Moreno-Altamirano MM, Prado-Garcia H and Sanchez-Garcia FJ (2016) Lactate Contribution to the Tumor Microenvironment: Mechanisms, Effects on Immune Cells and Therapeutic Relevance. Front Immunol 7, 52
  127. Penny HL, Sieow JL, Adriani G et al (2016) Warburg metabolism in tumor-conditioned macrophages promotes metastasis in human pancreatic ductal adenocarcinoma. Oncoimmunology 5, e1191731 https://doi.org/10.1080/2162402X.2016.1191731
  128. Wenes M, Shang M, Di Matteo M et al (2016) Macrophage Metabolism Controls Tumor Blood Vessel Morphogenesis and Metastasis. Cell Metab 24, 701-715 https://doi.org/10.1016/j.cmet.2016.09.008
  129. Movahedi K, Laoui D, Gysemans C et al (2010) Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Res 70, 5728-5739 https://doi.org/10.1158/0008-5472.CAN-09-4672
  130. Park JE, Dutta B, Tse SW et al (2019) Hypoxia-induced tumor exosomes promote M2-like macrophage polarization of infiltrating myeloid cells and microRNAmediated metabolic shift. Oncogene [Epub ahead of print]
  131. Pyonteck SM, Akkari L, Schuhmacher AJ et al (2013) CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med 19, 1264-1272 https://doi.org/10.1038/nm.3337
  132. Casazza A, Laoui D, Wenes M et al (2013) Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity. Cancer Cell 24, 695-709 https://doi.org/10.1016/j.ccr.2013.11.007
  133. Ouimet M, Ediriweera HN, Gundra UM et al (2015) MicroRNA-33-dependent regulation of macrophage metabolism directs immune cell polarization in atherosclerosis. J Clin Invest 125, 4334-4348 https://doi.org/10.1172/JCI81676
  134. Liu M, O'Connor RS, Trefely S, Graham K, Snyder NW and Beatty GL (2019) Metabolic rewiring of macrophages by CpG potentiates clearance of cancer cells and overcomes tumor-expressed CD47-mediated 'don't-eat-me' signal. Nat Immunol 20, 265-275 https://doi.org/10.1038/s41590-018-0292-y
  135. Miller AM, Asquith DL, Hueber AJ et al (2010) Interleukin-33 induces protective effects in adipose tissue inflammation during obesity in mice. Circ Res 107, 650-658 https://doi.org/10.1161/CIRCRESAHA.110.218867
  136. Rombaldova M, Janovska P, Kopecky J and Kuda O (2017) Omega-3 fatty acids promote fatty acid utilization and production of pro-resolving lipid mediators in alternatively activated adipose tissue macrophages. Biochem Biophys Res Commun 490, 1080-1085 https://doi.org/10.1016/j.bbrc.2017.06.170
  137. Furukawa S, Fujita T, Shimabukuro M et al (2004) Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 114, 1752-1761 https://doi.org/10.1172/JCI21625
  138. Xu J, Chi F, Guo T et al (2015) NOTCH reprograms mitochondrial metabolism for proinflammatory macrophage activation. J Clin Invest 125, 1579-1590 https://doi.org/10.1172/JCI76468
  139. Jung MJ, Lee J, Shin NR et al (2016) Chronic Repression of mTOR Complex 2 Induces Changes in the Gut Microbiota of Diet-induced Obese Mice. Sci Rep 6, 30887 https://doi.org/10.1038/srep30887
  140. Spann NJ, Garmire LX, McDonald JG et al (2012) Regulated accumulation of desmosterol integrates macrophage lipid metabolism and inflammatory responses. Cell 151, 138-152 https://doi.org/10.1016/j.cell.2012.06.054
  141. Deng J, Lu S, Liu H et al (2017) Homocysteine Activates B Cells via Regulating PKM2-Dependent Metabolic Reprogramming. J Immunol 198, 170-183 https://doi.org/10.4049/jimmunol.1600613
  142. Liao X, Sluimer JC, Wang Y et al (2012) Macrophage autophagy plays a protective role in advanced atherosclerosis. Cell Metab 15, 545-553 https://doi.org/10.1016/j.cmet.2012.01.022