Abstract
Macrophages develop into specialized cell types with special functional properties, depending on locally produced stimuli. Adipose tissue macrophages present particular characteristics, such as the M2 cell phenotype, and produce cytokines and chemokines usually produced by M1 cells. Our aim was to study the role of leptin, which is an adipokine produced and released by adipocytes, in the induction of these characteristics in macrophages found in the adipose tissue. Human CD14+ cells were obtained and maintained in culture with IFN-γ (classical M1 phenotype), IL-4 (alternative M2 phenotype) or leptin for 5 d. Surface marker expression was then analyzed by cytometry. In addition, the release of tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, IL-1β, IL-10, IL-1ra, MCP-1, MIP-1α, and RANTES was quantified by ELISA after an LPS stimulus, in the culture supernatant. Macrophages exposed to leptin in culture expressed surface markers that were more similar to the M2 phenotype, but they were able to produce TNF-α, IL-6, IL-1β, IL-1ra, IL-10, MCP-1, and MIP-1α, as observed for M1 cells. Results suggest that leptin strongly contributes to the phenotype observed in macrophages found in adipose tissue.
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Cheng X.; Wang J.; Xia N.; Yan X. X.; Tang T. T.; Chen H.; Zhang H. J.; Liu J.; Kong W.; Sjöberg S.; Folco E.; Libby P.; Liao Y. H.; Shi G. P. A guanidine-rich regulatory oligodeoxynucleotide improves type-2 diabetes in obese mice by blocking T-cell differentiation. EMBO Mol. Med. 4: 1112–1125; 2012.
Coppari R.; Bjørbæk C. Leptin revisited: its mechanism of action and potential for treating diabetes. Nat. Rev. Drug Discov. 11: 692–708; 2012.
Cousin B.; André M.; Casteilla L.; Pénicaud L. Altered macrophage-like functions of preadipocytes in inflammation and genetic obesity. J. Cell. Physiol. 186: 380–386; 2001.
Gabay C.; Dreyer M.; Pellegrinelli N.; Chicheportiche R.; Meier C. A. Leptin directly induces the secretion of interleukin 1 receptor antagonist in human monocytes. J. Clin. Endocrinol. Metab. 86: 783–791; 2001.
Geissmann F.; Manz M. G.; Jung S.; Sieweke M. H.; Merad M.; Ley K. Development of monocytes, macrophages, and dendritic cells. Science 327: 656–661; 2010.
Gordon S. Alternative activation of macrophages. Nat. Rev. Immunol. 3: 23–35; 2003.
Gruen M. L.; Hao M.; Piston D. W.; Hasty A. H. Leptin requires canonical migratory signaling pathways for induction of monocyte and macrophage chemotaxis. Am. J. Physiol. Cell Physiol. 293: C1481–C1488; 2007.
Karvonen-Gutierrez C. A.; Harlow S. D.; Mancuso P.; Jacobson J.; de Leon C. F.; Nan B. Leptin levels are associated with radiographic knee osteoarthritis among a cohort of mid-life women. Arthritis Care Res. 2012. doi:10.1002/acr.21922.
Kiguchi N.; Maeda T.; Kobayashi Y.; Fukazawa Y.; Kishioka S. Leptin enhances CC-chemokine ligand expression in cultured murine macrophage. Biochem. Biophys. Res. Commun. 384: 311–315; 2009.
Lumeng C. N.; Bodzin J. L.; Saltiel A. R. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J. Clin. Invest. 117: 175–184; 2007.
Lumeng C. N.; DelProposto J. B.; Westcott D. J.; Saltiel A. R. Phenotypic switching of adipose tissue macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes. Diabetes 57: 3239–3246; 2008.
Mouzaki A.; Panagoulias I.; Dervilli Z.; Zolota V.; Spadidea P.; Rodi M.; Panitsas F. P.; Lagadinou E.; de Lastic A. L.; Georgakopoulos T. Expression patterns of leptin receptor (OB-R) isoforms and direct in vitro effects of recombinant leptin on OB-R, leptin expression and cytokine secretion by human hematopoietic malignant cells. Cytokine 48: 203–211; 2009.
Munder M.; Eichmann K.; Modolell M. Alternative metabolic states in murine macrophages reflected by the nitric oxide synthase/arginase balance: competitive regulation by CD4+ T cells correlates with Th1/Th2 phenotype. J.Immunol. 160: 5347–5354; 1998.
Nguyen M. T.; Favelyukis S.; Nguyen A. K.; Reichart D.; Scott P. A.; Jenn A.; Liu-Bryan R.; Glass C. K.; Neels J. G.; Olefsky J. M. A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via Toll-like receptors 2 and 4 and JNK-dependent pathways. J. Biol. Chem. 282: 35279–35292; 2007.
Romeo G. R.; Lee J.; Shoelson S. E. Metabolic syndrome, insulin resistance, and roles of inflammation—mechanisms and therapeutic targets. Arterioscler. Thromb. Vasc. Biol. 32: 1771–1776; 2012.
Sahin D. S.; Tumer C.; Demir C.; Celik M. M.; Celik M.; Ucar E.; Gunesacar R. Association with leptin gene c.-2548 G>A polymorphism, serum leptin levels, and body mass index in Turkish obese patients. Cell. Biochem. Biophys. 2012. doi:10.1007/s12013-012-9427-1.
Santos-Alvarez J.; Goberna R.; Sánchez-Margalet V. Human leptin stimulates proliferation and activation of human circulating monocytes. Cell. Immunol. 194: 6–11; 1999.
Schroeter M. R.; Schneiderman J.; Schumann B.; Glückermann R.; Grimmas P.; Buchwald A. B.; Tirilomis T.; Schöndube F. A.; Konstantinides S. V.; Schäfer K. Expression of the leptin receptor in different types of vascular lesions. Histochem. Cell Biol. 128: 323–333; 2007.
Shaul M. E.; Bennett G.; Strissel K. J.; Greenberg A. S.; Obin M. S. Dynamic, M2-like remodeling phenotypes of CD11c+ adipose tissue macrophages during high-fat diet–induced obesity in mice. Diabetes 59: 1171–1181; 2010.
Sica A.; Mantovani A. Macrophage plasticity and polarization: in vivo veritas. Clin. Investig. 122: 787–795; 2012.
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. 25: 2062–2068; 2005.
Tarzi R. M.; Cook H. T.; Jackson I.; Pusey C. D.; Lord G. M. Leptin-deficient mice are protected from accelerated nephrotoxic nephritis. Am. J. Pathol. 164: 385–390; 2004.
Verschoor C. P.; Puchta A.; Bowdish D. M. The macrophage. Methods Mol. Biol. 844: 139–156; 2012.
Weisberg S. P.; Hunter D.; Huber R.; Lemieux J.; Slaymaker S.; Vaddi K.; Charo I.; Leibel R. L.; Ferrante Jr. A. W. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J. Clin. Invest. 116: 115–124; 2006.
Zeyda M.; Farmer D.; Todoric J.; Aszmann O.; Speiser M.; Györi G.; Zlabinger G. J.; Stulnig T. M. Human adipose tissue macrophages are of an anti-inflammatory phenotype but capable of excessive pro-inflammatory mediator production. Int. J. Obes. 31: 1420–1428; 2007.
Zhang Y.; Proenca R.; Maffei M.; Barone M.; Leopold L.; Friedman J. M. Positional cloning of the mouse obese gene and its human homologue. Nature 372: 425–432; 1994.
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This work was supported by a grant of FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo).
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Editor: T. Okamoto
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Acedo, S.C., Gambero, S., Cunha, F.G.P. et al. Participation of leptin in the determination of the macrophage phenotype: an additional role in adipocyte and macrophage crosstalk. In Vitro Cell.Dev.Biol.-Animal 49, 473–478 (2013). https://doi.org/10.1007/s11626-013-9629-x
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DOI: https://doi.org/10.1007/s11626-013-9629-x