BACKGROUND AND AIMS: Macrophages play important roles in adipose tissue inflammation and its consequences. Unfortunately, a detailed description of the macrophage phenotypes in different human adipose tissues is not available. SUBJECTS AND METHODS: Subcutaneous, visceral and perivascular adipose tissues were obtained from 52 living kidney donors during live donor nephrectomy. Stromal vascular fractions were isolated, and the macrophage phenotypes were analyzed by flow cytometry using surface markers (CD14, CD16, CD36, and CD163). RESULTS: In addition to CD16 positivity, pro-inflammatory macrophages also display high scavenger receptor CD36 expression. The great majority of CD16 negative macrophages express the anti-inflammatory CD163 marker. The presence of pro-inflammatory macrophages was almost twice as high in visceral (p < 0.0001) and perivascular (p < 0.0001) adipose tissues than in subcutaneous tissue. This difference was substantially more pronounced in the postmenopausal women subgroup, consequentlly, the total difference was driven by this subgroup. CONCLUSION: We obtained detailed information about M1 and M2 macrophage phenotypes in human adipose tissue. The visceral and perivascular adipose tissues had substantially higher pro-inflammatory characteristics than the subcutaneous tissue. The higher proportion of pro-inflammatory macrophages in the visceral adipose tissue of postmenopausal women might be related to an increased cardiovascular risk.

2nd Faculty of Medicine Charles University Prague Prague Czech Republic

Department of Clinical and Transplant Immunology Institute for Clinical and Experimental Medicine Prague Czech Republic

Laboratory for Atherosclerosis Research Centre for Experimental Medicine Institute for Clinical and Experimental Medicine Prague Czech Republic

Transplant Surgery Department Institute for Clinical and Experimental Medicine Prague Czech Republic

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McNelis JC, Olefsky JM. Macrophages, immunity, and metabolic disease. Immunity. 2014;41:36–48. doi: 10.1016/j.immuni.2014.05.010. PubMed DOI

Funahashi T, Nakamura T, Shimomura I, Maeda K, Kuriyama H, Takahashi M, Arita Y, Kihara S, Matsuzawa Y. Role of adipocytokines on the pathogenesis of atherosclerosis in visceral obesity. Intern Med. 1999;38:202–206. doi: 10.2169/internalmedicine.38.202. PubMed DOI

Libby P. Inflammatory mechanisms: the molecular basis of inflammation and disease. Nutr Rev. 2007;65:S140–S146. doi: 10.1301/nr.2007.dec.S140-S146. PubMed DOI

Bourlier V, Zakaroff-Girard A, Miranville A, De Barros S, Maumus M, Sengenes C, Galitzky J, Lafontan M, Karpe F, Frayn KN, Bouloumie A. Remodeling phenotype of human subcutaneous adipose tissue macrophages. Circulation. 2008;117:806–815. doi: 10.1161/CIRCULATIONAHA.107.724096. PubMed DOI

Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003;112:1821–1830. doi: 10.1172/JCI200319451. PubMed DOI PMC

Fjeldborg K, Pedersen SB, Moller HJ, Christiansen T, Bennetzen M, Richelsen B. Human adipose tissue macrophages are enhanced but changed to an anti-inflammatory profile in obesity. J Immunol Res. 2014;2014:309548. doi: 10.1155/2014/309548. PubMed DOI PMC

Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW., Jr Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112:1796–1808. doi: 10.1172/JCI200319246. PubMed DOI PMC

Chawla A, Nguyen KD, Goh YP. Macrophage-mediated inflammation in metabolic disease. Nat Rev Immunol. 2011;11:738–749. doi: 10.1038/nri3071. PubMed DOI PMC

Suganami T, Nishida J, Ogawa Y. A paracrine loop between adipocytes and macrophages aggravates inflammatory changes: role of free fatty acids and tumor necrosis factor alpha. Arterioscler Thromb Vasc Biol. 2005;25:2062–2068. doi: 10.1161/01.ATV.0000183883.72263.13. PubMed DOI

Ramkhelawon B, Hennessy EJ, Menager M, Ray TD, Sheedy FJ, Hutchison S, Wanschel A, Oldebeken S, Geoffrion M, Spiro W, et al. Netrin-1 promotes adipose tissue macrophage retention and insulin resistance in obesity. Nat Med. 2014;20:377–384. doi: 10.1038/nm.3467. PubMed DOI PMC

Amano SU, Cohen JL, Vangala P, Tencerova M, Nicoloro SM, Yawe JC, Shen Y, Czech MP, Aouadi M. Local proliferation of macrophages contributes to obesity-associated adipose tissue inflammation. Cell Metab. 2014;19:162–171. doi: 10.1016/j.cmet.2013.11.017. PubMed DOI PMC

Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S, Gordon S, Hamilton JA, Ivashkiv LB, Lawrence T, et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity. 2014;41:14–20. doi: 10.1016/j.immuni.2014.06.008. PubMed DOI PMC

Martinez FO, Sica A, Mantovani A, Locati M. Macrophage activation and polarization. Front Biosci. 2008;13:453–461. doi: 10.2741/2692. PubMed DOI

Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest. 2007;117:175–184. doi: 10.1172/JCI29881. PubMed DOI PMC

Shaul ME, Bennett G, Strissel KJ, Greenberg AS, Obin MS. Dynamic, M2-like remodeling phenotypes of CD11c + adipose tissue macrophages during high-fat diet–induced obesity in mice. Diabetes. 2010;59:1171–1181. doi: 10.2337/db09-1402. PubMed DOI PMC

Kawanishi N, Yano H, Yokogawa Y, Suzuki K. Exercise training inhibits inflammation in adipose tissue via both suppression of macrophage infiltration and acceleration of phenotypic switching from M1 to M2 macrophages in high-fat-diet-induced obese mice. Exerc Immunol Rev. 2010;16:105–118. PubMed

Oliveira AG, Araujo TG, Carvalho BM, Guadagnini D, Rocha GZ, Bagarolli RA, Carvalheira JB, Saad MJ. Acute exercise induces a phenotypic switch in adipose tissue macrophage polarization in diet-induced obese rats. Obesity (Silver Spring) 2013;21:2545–2556. doi: 10.1002/oby.20402. PubMed DOI

Kovacikova M, Sengenes C, Kovacova Z, Siklova-Vitkova M, Klimcakova E, Polak J, Rossmeislova L, Bajzova M, Hejnova J, Hnevkovska Z, et al. Dietary intervention-induced weight loss decreases macrophage content in adipose tissue of obese women. Int J Obes (Lond) 2011;35:91–98. doi: 10.1038/ijo.2010.112. PubMed DOI

Zeyda M, Farmer D, Todoric J, Aszmann O, Speiser M, Gyori G, Zlabinger GJ, Stulnig TM. Human adipose tissue macrophages are of an anti-inflammatory phenotype but capable of excessive pro-inflammatory mediator production. Int J Obes (Lond) 2007;31:1420–1428. doi: 10.1038/sj.ijo.0803632. PubMed DOI

Aron-Wisnewsky J, Tordjman J, Poitou C, Darakhshan F, Hugol D, Basdevant A, Aissat A, Guerre-Millo M, Clement K. Human adipose tissue macrophages: m1 and m2 cell surface markers in subcutaneous and omental depots and after weight loss. J Clin Endocrinol Metab. 2009;94:4619–4623. doi: 10.1210/jc.2009-0925. PubMed DOI

Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, Benhaim P, Lorenz HP, Hedrick MH. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 2001;7:211–228. doi: 10.1089/107632701300062859. PubMed DOI

Barros MH, Hauck F, Dreyer JH, Kempkes B, Niedobitek G. Macrophage polarisation: an immunohistochemical approach for identifying M1 and M2 macrophages. PLoS One. 2013;8:e80908. doi: 10.1371/journal.pone.0080908. PubMed DOI PMC

Buechler C, Eisinger K, Krautbauer S. Diagnostic and prognostic potential of the macrophage specific receptor CD163 in inflammatory diseases. Inflamm Allergy Drug Targets. 2013;12:391–402. doi: 10.2174/18715281113126660060. PubMed DOI

Kratz M, Coats BR, Hisert KB, Hagman D, Mutskov V, Peris E, Schoenfelt KQ, Kuzma JN, Larson I, Billing PS, et al. Metabolic dysfunction drives a mechanistically distinct proinflammatory phenotype in adipose tissue macrophages. Cell Metab. 2014;20:614–625. doi: 10.1016/j.cmet.2014.08.010. PubMed DOI PMC

Kralova Lesna I, Poledne R, Fronek J, Kralova A, Sekerkova A, Thieme F, Pitha J. Macrophage subsets in the adipose tissue could be modified by sex and the reproductive age of women. Atherosclerosis. 2015;241:255–258. doi: 10.1016/j.atherosclerosis.2015.03.018. PubMed DOI

Kraunsoe R, Boushel R, Hansen CN, Schjerling P, Qvortrup K, Stockel M, Mikines KJ, Dela F. Mitochondrial respiration in subcutaneous and visceral adipose tissue from patients with morbid obesity. J Physiol. 2010;588:2023–2032. doi: 10.1113/jphysiol.2009.184754. PubMed DOI PMC

Rose S, Stansky E, Dagur PK, Samsel L, Weiner E, Jahanshad A, Doveikis J, Naik HB, Playford MP, McCoy JP, Mehta NN. Characterization of immune cells in psoriatic adipose tissue. J Transl Med. 2014;12:258. doi: 10.1186/s12967-014-0258-2. PubMed DOI PMC

Alessio M, De Monte L, Scirea A, Gruarin P, Tandon NN, Sitia R. Synthesis, processing, and intracellular transport of CD36 during monocytic differentiation. J Biol Chem. 1996;271:1770–1775. doi: 10.1074/jbc.271.3.1770. PubMed DOI

Jiang Y, Wang M, Huang K, Zhang Z, Shao N, Zhang Y, Wang W, Wang S. Oxidized low-density lipoprotein induces secretion of interleukin-1beta by macrophages via reactive oxygen species-dependent NLRP3 inflammasome activation. Biochem Biophys Res Commun. 2012;425:121–126. doi: 10.1016/j.bbrc.2012.07.011. PubMed DOI

Park YM. CD36, a scavenger receptor implicated in atherosclerosis. Exp Mol Med. 2014;46:e99. doi: 10.1038/emm.2014.38. PubMed DOI PMC

Larter CZ, Yeh MM, Haigh WG, Van Rooyen DM, Brooling J, Heydet D, Nolan CJ, Teoh NC, Farrell GC. Dietary modification dampens liver inflammation and fibrosis in obesity-related fatty liver disease. Obesity (Silver Spring) 2013;21:1189–1199. doi: 10.1002/oby.20123. PubMed DOI

Edin S, Wikberg ML, Dahlin AM, Rutegard J, Oberg A, Oldenborg PA, Palmqvist R. The distribution of macrophages with a M1 or M2 phenotype in relation to prognosis and the molecular characteristics of colorectal cancer. PLoS One. 2012;7:e47045. doi: 10.1371/journal.pone.0047045. PubMed DOI PMC

Kaku Y, Imaoka H, Morimatsu Y, Komohara Y, Ohnishi K, Oda H, Takenaka S, Matsuoka M, Kawayama T, Takeya M, Hoshino T. Overexpression of CD163, CD204 and CD206 on alveolar macrophages in the lungs of patients with severe chronic obstructive pulmonary disease. PLoS One. 2014;9:e87400. doi: 10.1371/journal.pone.0087400. PubMed DOI PMC

Vogel DY, Glim JE, Stavenuiter AW, Breur M, Heijnen P, Amor S, Dijkstra CD, Beelen RH. Human macrophage polarization in vitro: maturation and activation methods compared. Immunobiology. 2014;219:695–703. doi: 10.1016/j.imbio.2014.05.002. PubMed DOI

Moestrup SK, Moller HJ. CD163: a regulated hemoglobin scavenger receptor with a role in the anti-inflammatory response. Ann Med. 2004;36:347–354. doi: 10.1080/07853890410033171. PubMed DOI

Chinetti-Gbaguidi G, Colin S, Staels B. Macrophage subsets in atherosclerosis. Nat Rev Cardiol. 2015;12:10–17. doi: 10.1038/nrcardio.2014.173. PubMed DOI

Morris DL, Singer K, Lumeng CN. Adipose tissue macrophages: phenotypic plasticity and diversity in lean and obese states. Curr Opin Clin Nutr Metab Care. 2011;14:341–346. doi: 10.1097/MCO.0b013e328347970b. PubMed DOI PMC

Cifkova R, Skodova Z, Bruthans J, Adamkova V, Jozifova M, Galovcova M, Wohlfahrt P, Krajcoviechova A, Poledne R, Stavek P, Lanska V. Longitudinal trends in major cardiovascular risk factors in the Czech population between 1985 and 2007/8. Czech MONICA and Czech post-MONICA. Atherosclerosis. 2010;211:676–681. doi: 10.1016/j.atherosclerosis.2010.04.007. PubMed DOI

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