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Archives of Pharmacal Research

, Volume 36, Issue 2, pp 208–222 | Cite as

Adipose tissue macrophages in the development of obesity-induced inflammation, insulin resistance and type 2 Diabetes

  • Jongsoon LeeEmail author
Review

Abstract

It has been increasingly accepted that chronic subacute inflammation plays an important role in the development of insulin resistance and type 2 Diabetes in animals and humans. Particularly supporting this is that suppression of systemic inflammation in type 2 Diabetes improves glycemic control; this also points to a new potential therapeutic target for the treatment of type 2 Diabetes. Recent studies strongly suggest that obesity-induced inflammation is mainly mediated by tissue resident immune cells, with particular attention being focused on adipose tissue macrophages (ATMs). This review delineates the current progress made in understanding obesity-induced inflammation and the roles ATMs play in this process.

Keywords

Adipose tissue macrophage (ATM) Insulin resistance Obesity Inflammation 

Notes

Acknowledgments

The author was supported by grants from the American Diabetes Association (RA 110BS97), Pilot and Feasibility awards from the Boston Obesity Nutrition Research Center (DK046200, NIDDK) and NIH/NIDDK (DK80380).

References

  1. Aljada, A., P. Mohanty, H. Ghanim, T. Abdo, D. Tripathy, A. Chaudhuri, and P. Dandona. 2004. Increase in intranuclear nuclear factor kappaB and decrease in inhibitor kappaB in mononuclear cells after a mixed meal: Evidence for a proinflammatory effect. American Journal of Clinical Nutrition 79: 682–690.PubMedGoogle Scholar
  2. Amulic, B., C. Cazalet, G.L. Hayes, K.D. Metzler, and A. Zychlinsky. 2012. Neutrophil function: From mechanisms to disease. Annual Review of Immunology 30: 459–489.PubMedCrossRefGoogle Scholar
  3. Angeli, V., J. Llodra, J.X. Rong, K. Satoh, S. Ishii, T. Shimizu, E.A. Fisher, and G.J. Randolph. 2004. Dyslipidemia associated with atherosclerotic disease systemically alters dendritic cell mobilization. Immunity 21: 561–574.PubMedCrossRefGoogle Scholar
  4. Aouadi, M., G.J. Tesz, S.M. Nicoloro, M. Wang, M. Chouinard, E. Soto, G.R. Ostroff, and M.P. Czech. 2009. Orally delivered siRNA targeting macrophage Map4k4 suppresses systemic inflammation. Nature 458: 1180–1184.PubMedCrossRefGoogle Scholar
  5. Arkan, M.C., A.L. Hevener, F.R. Greten, S. Maeda, Z.W. Li, J.M. Long, A. Wynshaw-Boris, G. Poli, J. Olefsky, and M. Karin. 2005. IKK-beta links inflammation to obesity-induced insulin resistance. Nature Medicine 11: 191–198.PubMedCrossRefGoogle Scholar
  6. Baeuerle, P.A., and D. Baltimore. 1996. NF-kappa B: Ten years after. Cell 87: 13–20.PubMedCrossRefGoogle Scholar
  7. Barzilay, J.I., L. Abraham, S.R. Heckbert, M. Cushman, L.H. Kuller, H.E. Resnick, and R.P. Tracy. 2001. The relation of markers of inflammation to the development of glucose disorders in the elderly: The Cardiovascular Health Study. Diabetes 50: 2384–2389.PubMedCrossRefGoogle Scholar
  8. Barzilay, J., and E. Freedland. 2003. Inflammation and its association with glucose disorders and cardiovascular disease. Treatments in Endocrinology 2: 85–94.PubMedCrossRefGoogle Scholar
  9. Bhatt, B.A., J.J. Dube, N. Dedousis, J.A. Reider, and R.M. O’doherty. 2006. Diet-induced obesity and acute hyperlipidemia reduce IkappaBalpha levels in rat skeletal muscle in a fiber-type dependent manner. American Journal of Physiology 290: R233–R240.PubMedGoogle Scholar
  10. Biddinger, S.B., and C.R. Kahn. 2006. From mice to men: Insights into the insulin resistance syndromes. Annual Review of Physiology 68: 123–158.PubMedCrossRefGoogle Scholar
  11. Boden, G. 2006. Fatty acid-induced inflammation and insulin resistance in skeletal muscle and liver. Current Diabetes Reports 6: 177–181.PubMedCrossRefGoogle Scholar
  12. Bourlier, V., A. Zakaroff-Girard, A. Miranville, S. De Barros, M. Maumus, C. Sengenes, J. Galitzky, M. Lafontan, F. Karpe, K.N. Frayn, and A. Bouloumie. 2008. Remodeling phenotype of human subcutaneous adipose tissue macrophages. Circulation 117: 806–815.PubMedCrossRefGoogle Scholar
  13. Cai, D., D. Frantz, M. Iwamoto, M. Yuan, J. Lee, and S.E. Shoelson. 2002. Fat-specific expression of activated IKKβ causes insulin resistance in mice. Diabetes 51(Supplement 2): A57.Google Scholar
  14. Cai, D., J.D. Frantz, N.E. Tawa Jr., P.A. Melendez, B.C. Oh, H.G. Lidov, P.O. Hasselgren, W.R. Frontera, J. Lee, D.J. Glass, and S.E. Shoelson. 2004. IKKbeta/NF-kappaB activation causes severe muscle wasting in mice. Cell 119: 285–298.PubMedCrossRefGoogle Scholar
  15. Cai, D., D. Frantz, M. Yuan, P.A. Melendez, J. Lee, and S.E. Shoelson. 2005. Local and systemic insulin resistance due to hepatic activation of IKKα and NF-κB. Nature Medicine 11: 183–190.PubMedCrossRefGoogle Scholar
  16. Cancello, R., C. Henegar, N. Viguerie, S. Taleb, C. Poitou, C. Rouault, M. Coupaye, V. Pelloux, D. Hugol, J.L. Bouillot, A. Bouloumie, G. Barbatelli, S. Cinti, P.A. Svensson, G.S. Barsh, J.D. Zucker, A. Basdevant, D. Langin, and K. Clement. 2005. Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss. Diabetes 54: 2277–2286.PubMedCrossRefGoogle Scholar
  17. Caricilli, A.M., P.K. Picardi, L.L. De Abreu, M. Ueno, P.O. Prada, E.R. Ropelle, S.M. Hirabara, A. Castoldi, P. Vieira, N.O. Camara, R. Curi, J.B. Carvalheira, and M.J. Saad. 2011. Gut microbiota is a key modulator of insulin resistance in TLR 2 knockout mice. PLoS Biology 9: e1001212.PubMedCrossRefGoogle Scholar
  18. Chavey, C., G. Lazennec, S. Lagarrigue, C. Clape, I. Iankova, J. Teyssier, J.S. Annicotte, J. Schmidt, C. Mataki, H. Yamamoto, R. Sanches, A. Guma, V. Stich, M. Vitkova, B. Jardin-Watelet, E. Renard, R. Strieter, A. Tuthill, G.S. Hotamisligil, A. Vidal-Puig, A. Zorzano, D. Langin, and L. Fajas. 2009. CXC ligand 5 is an adipose-tissue derived factor that links obesity to insulin resistance. Cell Metabolism 9: 339–349.PubMedCrossRefGoogle Scholar
  19. Chawla, A., K.D. Nguyen, and Y.P. Goh. 2011. Macrophage-mediated inflammation in metabolic disease. Nature Reviews Immunology 11: 738–749.PubMedCrossRefGoogle Scholar
  20. Chen, G.Y., and G. Nunez. 2010. Sterile inflammation: Sensing and reacting to damage. Nature Reviews Immunology 10: 826–837.PubMedCrossRefGoogle Scholar
  21. Cinti, S., G. Mitchell, G. Barbatelli, I. Murano, E. Ceresi, E. Faloia, S. Wang, M. Fortier, A.S. Greenberg, and M.S. Obin. 2005. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. Journal of Lipid Research 46: 2347–2355.PubMedCrossRefGoogle Scholar
  22. Curat, C.A., A. Miranville, C. Sengenes, M. Diehl, C. Tonus, R. Busse, and A. Bouloumie. 2004. From blood monocytes to adipose tissue-resident macrophages: Induction of diapedesis by human mature adipocytes. Diabetes 53: 1285–1292.PubMedCrossRefGoogle Scholar
  23. Dandona, P., A. Aljada, and A. Bandyopadhyay. 2004. Inflammation: The link between insulin resistance, obesity and diabetes. Trends in Immunology 25: 4–7.PubMedCrossRefGoogle Scholar
  24. Davis, B.K., H. Wen, and J.P. Ting. 2011. The inflammasome NLRs in immunity, inflammation, and associated diseases. Annual Review of Immunology 29: 707–735.PubMedCrossRefGoogle Scholar
  25. De Celsus, A.C. 1971. Medicina. Cambridge: Harvard University Press.Google Scholar
  26. Di Gregorio, G.B., A. Yao-Borengasser, N. Rasouli, V. Varma, T. Lu, L.M. Miles, G. Ranganathan, C.A. Peterson, R.E. Mcgehee, and P.A. Kern. 2005. Expression of CD68 and macrophage chemoattractant protein-1 genes in human adipose and muscle tissues: Association with cytokine expression, insulin resistance, and reduction by pioglitazone. Diabetes 54: 2305–2313.PubMedCrossRefGoogle Scholar
  27. Didonato, J.A., M. Hayakawa, D.M. Rothwarf, E. Zandi, and M. Karin. 1997. A cytokine-responsive IκB kinase that activates the transcription factor NF-κB. Nature 388: 548–554.PubMedCrossRefGoogle Scholar
  28. Donath, M.Y., and S.E. Shoelson. 2011. Type 2 diabetes as an inflammatory disease. Nature Reviews Immunology 11: 98–107.PubMedCrossRefGoogle Scholar
  29. Duewell, P., H. Kono, K.J. Rayner, C.M. Sirois, G. Vladimer, F.G. Bauernfeind, G.S. Abela, L. Franchi, G. Nunez, M. Schnurr, T. Espevik, E. Lien, K.A. Fitzgerald, K.L. Rock, K.J. Moore, S.D. Wright, V. Hornung, and E. Latz. 2010. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464: 1357–1361.PubMedCrossRefGoogle Scholar
  30. Duncan, B.B., M.I. Schmidt, J.S. Pankow, C.M. Ballantyne, D. Couper, A. Vigo, R. Hoogeveen, A.R. Folsom, and G. Heiss. 2003. Low-grade systemic inflammation and the development of type 2 diabetes: The atherosclerosis risk in communities study. Diabetes 52: 1799–1805.PubMedCrossRefGoogle Scholar
  31. Festa, A., R. D’agostino Jr., G. Howard, L. Mykkanen, R.P. Tracy, and S.M. Haffner. 2000. Chronic subclinical inflammation as part of the insulin resistance syndrome: The Insulin Resistance Atherosclerosis Study (IRAS). Circulation 102: 42–47.PubMedCrossRefGoogle Scholar
  32. Feuerer, M., L. Herrero, D. Cipolletta, A. Naaz, J. Wong, A. Nayer, J. Lee, A.B. Goldfine, C. Benoist, S. Shoelson, and D. Mathis. 2009. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nature Medicine 15: 930–939.PubMedCrossRefGoogle Scholar
  33. Ford, E.S. 2002. Leukocyte count, erythrocyte sedimentation rate, and diabetes incidence in a national sample of US adults. American Journal of Epidemiology 155: 57–64.PubMedCrossRefGoogle Scholar
  34. Freeman, D.J., J. Norrie, M.J. Caslake, A. Gaw, I. Ford, G.D. Lowe, D.S. O’reilly, C.J. Packard, and N. Sattar. 2002. C-reactive protein is an independent predictor of risk for the development of diabetes in the West of Scotland Coronary Prevention Study. Diabetes 51: 1596–1600.PubMedCrossRefGoogle Scholar
  35. Gautier, E.L., T. Shay, J. Miller, M. Greter, C. Jakubzick, S. Ivanov, J. Helft, A. Chow, K.G. Elpek, S. Gordonov, A.R. Mazloom, A. Ma’ayan, W.J. Chua, T.H. Hansen, S.J. Turley, M. Merad, G.J. Randolph, A.J. Best, J. Knell, A. Goldrath, B. Brown, V. Jojic, D. Koller, N. Cohen, P. Brennan, M. Brenner, A. Regev, A. Fletcher, K. Elpek, A. Bellemare-Pelletier, D. Malhotra, S. Turley, R. Jianu, D. Laidlaw, J. Collins, K. Narayan, K. Sylvia, J. Kang, R. Gazit, B.S. Garrison, D.J. Rossi, F. Kim, T.N. Rao, A. Wagers, S.A. Shinton, R.R. Hardy, P. Monach, N.A. Bezman, J.C. Sun, C.C. Kim, L.L. Lanier, T. Heng, T. Kreslavsky, M. Painter, J. Ericson, S. Davis, D. Mathis, and C. Benoist. 2012. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nature Immunology 13: 1118–1128.PubMedCrossRefGoogle Scholar
  36. Geissmann, F., S. Jung, and D.R. Littman. 2003. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19: 71–82.PubMedCrossRefGoogle Scholar
  37. Ghanim, H., R. Garg, A. Aljada, P. Mohanty, Y. Kumbkarni, E. Assian, W. Hamouda, and P. Dandona. 2001. Suppression of nuclear factor-kappaB and stimulation of inhibitor kappaB by troglitazone: Evidence for an anti-inflammatory effect and a potential antiatherosclerotic effect in the obese. Journal of Clinical Endocrinology and Metabolism 86: 1306–1312.PubMedCrossRefGoogle Scholar
  38. Goldfine, A.B., V. Fonseca, K.A. Jablonski, L. Pyle, M.A. Staten, and S.E. Shoelson. 2010. The effects of salsalate on glycemic control in patients with type 2 diabetes: A randomized trial. Annals of Internal Medicine 152: 346–357.PubMedGoogle Scholar
  39. Goldfine, A.B., R. Silver, A. Waleed, D. Cai, E. Tatro, J. Lee, and S.E. Shoelson. 2008. Use of salsalate to target inflammation in the treatment of insulin resistance and type 2 diabetes. Clinical Translation Science 1: 36–43.CrossRefGoogle Scholar
  40. Gordon, S. 2007. Macrophage heterogeneity and tissue lipids. The Journal of Clinical Investigation 117: 89–93.PubMedCrossRefGoogle Scholar
  41. Gordon, S., and P.R. Taylor. 2005. Monocyte and macrophage heterogeneity. Nature Reviews Immunology 5: 953–964.PubMedCrossRefGoogle Scholar
  42. Grage-Griebenow, E., H.D. Flad, and M. Ernst. 2001. Heterogeneity of human peripheral blood monocyte subsets. Journal of Leukocyte Biology 69: 11–20.PubMedGoogle Scholar
  43. Herrero, L., H. Shapiro, A. Nayer, J. Lee, and S.E. Shoelson. 2010. Inflammation and adipose tissue macrophages in lipodystrophic mice. Proceedings of the National Academy of Sciences of the United States of America 107: 240–245.PubMedCrossRefGoogle Scholar
  44. Hess, J., P. Angel, and M. Schorpp-Kistner. 2004. AP-1 subunits: Quarrel and harmony among siblings. Journal of Cell Science 117: 5965–5973.PubMedCrossRefGoogle Scholar
  45. Hevener, A.L., J.M. Olefsky, D. Reichart, M.T. Nguyen, G. Bandyopadyhay, H.Y. Leung, M.J. Watt, C. Benner, M.A. Febbraio, A.K. Nguyen, B. Folian, S. Subramaniam, F.J. Gonzalez, C.K. Glass, and M. Ricote. 2007. Macrophage PPAR gamma is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones. The Journal of Clinical Investigation 117: 1658–1669.PubMedCrossRefGoogle Scholar
  46. Hirosumi, J., G. Tuncman, L. Chang, C.Z. Gorgun, K.T. Uysal, K. Maeda, M. Karin, and G.S. Hotamisligil. 2002. A central role for JNK in obesity and insulin resistance. Nature 420: 333–336.PubMedCrossRefGoogle Scholar
  47. Hoffmann, A., T.H. Leung, and D. Baltimore. 2003. Genetic analysis of NF-kappaB/Rel transcription factors defines functional specificities. EMBO Journal 22: 5530–5539.PubMedCrossRefGoogle Scholar
  48. Hosoi, T., S. Yokoyama, S. Matsuo, S. Akira, and K. Ozawa. 2010. Myeloid differentiation factor 88 (MyD88)-deficiency increases risk of diabetes in mice. PLoS One 5: e12537.PubMedCrossRefGoogle Scholar
  49. Hotamisligil, G.S. 2006. Inflammation and metabolic disorders. Nature 444: 860–867.PubMedCrossRefGoogle Scholar
  50. Hotamisligil, G.S., N.S. Shargill, and B.M. Spiegelman. 1993. Adipose expression of tumor necrosis factor-α: Direct role in obesity-linked insulin resistance. Science 259: 87–91.PubMedCrossRefGoogle Scholar
  51. Huang, W., A. Metlakunta, N. Dedousis, P. Zhang, I. Sipula, J.J. Dube, D.K. Scott, and R.M. O’doherty. 2010. Depletion of liver Kupffer cells prevents the development of diet-induced hepatic steatosis and insulin resistance. Diabetes 59: 347–357.PubMedCrossRefGoogle Scholar
  52. Hundal, R.S., K.F. Petersen, A.B. Mayerson, P.S. Randhawa, S. Inzucchi, S.E. Shoelson, and G.I. Shulman. 2002. Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes. The Journal of Clinical Investigation 109: 1321–1326.PubMedGoogle Scholar
  53. Jaeschke, A., M.P. Czech, and R.J. Davis. 2004. An essential role of the JIP1 scaffold protein for JNK activation in adipose tissue. Genes & Development 18: 1976–1980.CrossRefGoogle Scholar
  54. Jenkins, S.J., D. Ruckerl, P.C. Cook, L.H. Jones, F.D. Finkelman, N. Van Rooijen, A.S. Macdonald, and J.E. Allen. 2011. Local macrophage proliferation, rather than recruitment from the blood, is a signature of TH2 inflammation. Science 332: 1284–1288.PubMedCrossRefGoogle Scholar
  55. Kamei, N., K. Tobe, R. Suzuki, M. Ohsugi, T. Watanabe, N. Kubota, N. Ohtsuka-Kowatari, K. Kumagai, K. Sakamoto, M. Kobayashi, T. Yamauchi, K. Ueki, Y. Oishi, S. Nishimura, I. Manabe, H. Hashimoto, Y. Ohnishi, H. Ogata, K. Tokuyama, M. Tsunoda, T. Ide, K. Murakami, R. Nagai, and T. Kadowaki. 2006. Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance. Journal of Biological Chemistry 281: 26602–26614.PubMedCrossRefGoogle Scholar
  56. Kanda, H., S. Tateya, Y. Tamori, K. Kotani, K. Hiasa, R. Kitazawa, S. Kitazawa, H. Miyachi, S. Maeda, K. Egashira, and M. Kasuga. 2006. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. The Journal of Clinical Investigation 116: 1494–1505.PubMedCrossRefGoogle Scholar
  57. Kang, K., S.M. Reilly, V. Karabacak, M.R. Gangl, K. Fitzgerald, B. Hatano, and C.H. Lee. 2008. Adipocyte-derived Th2 cytokines and myeloid PPARdelta regulate macrophage polarization and insulin sensitivity. Cell Metabolism 7: 485–495.PubMedCrossRefGoogle Scholar
  58. Karin, M. 2006. Role for IKK2 in muscle: Waste not, want not. The Journal of Clinical Investigation 116: 2866–2868.PubMedCrossRefGoogle Scholar
  59. Kim, H.J., T. Higashimori, S.Y. Park, H. Choi, J. Dong, Y.J. Kim, H.L. Noh, Y.R. Cho, G. Cline, Y.B. Kim, and J.K. Kim. 2004. Differential effects of interleukin-6 and -10 on skeletal muscle and liver insulin action in vivo. Diabetes 53: 1060–1067.PubMedCrossRefGoogle Scholar
  60. Kim, J.K., Y.J. Kim, J.J. Fillmore, Y. Chen, I. Moore, J. Lee, M. Yuan, Z.W. Li, M. Karin, P. Perret, S.E. Shoelson, and G.I. Shulman. 2001. Prevention of fat-induced insulin resistance by salicylate. The Journal of Clinical Investigation 108: 437–446.PubMedGoogle Scholar
  61. Klover, P.J., T.A. Zimmers, L.G. Koniaris, and R.A. Mooney. 2003. Chronic exposure to interleukin-6 causes hepatic insulin resistance in mice. Diabetes 52: 2784–2789.PubMedCrossRefGoogle Scholar
  62. Koliwad, S.K., R.S. Streeper, M. Monetti, I. Cornelissen, L. Chan, K. Terayama, S. Naylor, M. Rao, B. Hubbard, and R.V. Farese Jr. 2010. DGAT1-dependent triacylglycerol storage by macrophages protects mice from diet-induced insulin resistance and inflammation. The Journal of Clinical Investigation 120: 756–767.PubMedCrossRefGoogle Scholar
  63. Kosteli, A., E. Sugaru, G. Haemmerle, J.F. Martin, J. Lei, R. Zechner, and A.W. Ferrante Jr. 2010. Weight loss and lipolysis promote a dynamic immune response in murine adipose tissue. The Journal of Clinical Investigation 120: 3466–3479.PubMedCrossRefGoogle Scholar
  64. Kurokawa, J., H. Nagano, O. Ohara, N. Kubota, T. Kadowaki, S. Arai, and T. Miyazaki. 2011. Apoptosis inhibitor of macrophage (AIM) is required for obesity-associated recruitment of inflammatory macrophages into adipose tissue. Proceedings of the National Academy of Sciences of the United States of America 108: 12072–12077.PubMedCrossRefGoogle Scholar
  65. Lee, F.Y., Y. Li, E.K. Yang, S.Q. Yang, H.Z. Lin, M.A. Trush, A.J. Dannenberg, and A.M. Diehl. 1999. Phenotypic abnormalities in macrophages from leptin-deficient, obese mice. American Journal of Physiology 276: C386–C394.PubMedGoogle Scholar
  66. Lesniewski, L.A., S.E. Hosch, J.G. Neels, C. De Luca, M. Pashmforoush, C.N. Lumeng, S.H. Chiang, M. Scadeng, A.R. Saltiel, and J.M. Olefsky. 2007. Bone marrow-specific Cap gene deletion protects against high-fat diet-induced insulin resistance. Nature Medicine 13: 455–462.PubMedCrossRefGoogle Scholar
  67. Liang, C.P., S. Han, H. Okamoto, R. Carnemolla, I. Tabas, D. Accili, and A.R. Tall. 2004. Increased CD36 protein as a response to defective insulin signaling in macrophages. The Journal of Clinical Investigation 113: 764–773.PubMedGoogle Scholar
  68. Liao, X., N. Sharma, F. Kapadia, G. Zhou, Y. Lu, H. Hong, K. Paruchuri, G.H. Mahabeleshwar, E. Dalmas, N. Venteclef, C.A. Flask, J. Kim, B.W. Doreian, K.Q. Lu, K.H. Kaestner, A. Hamik, K. Clement, and M.K. Jain. 2011. Kruppel-like factor 4 regulates macrophage polarization. The Journal of Clinical Investigation 121: 2736–2749.PubMedCrossRefGoogle Scholar
  69. Liu, J., A. Divoux, J. Sun, J. Zhang, K. Clement, J.N. Glickman, G.K. Sukhova, P.J. Wolters, J. Du, C.Z. Gorgun, A. Doria, P. Libby, R.S. Blumberg, B.B. Kahn, G.S. Hotamisligil, and G.P. Shi. 2009. Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice. Nature Medicine 15: 940–945.PubMedCrossRefGoogle Scholar
  70. Lumeng, C.N., J.L. Bodzin, and A.R. Saltiel. 2007a. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. The Journal of Clinical Investigation 117: 175–184.PubMedCrossRefGoogle Scholar
  71. Lumeng, C.N., S.M. Deyoung, J.L. Bodzin, and A.R. Saltiel. 2007b. Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity. Diabetes 56: 16–23.PubMedCrossRefGoogle Scholar
  72. Mayi, T.H., M. Daoudi, B. Derudas, B. Gross, G. Bories, K. Wouters, J. Brozek, R. Caiazzo, V. Raverdi, M. Pigeyre, P. Allavena, A. Mantovani, F. Pattou, B. Staels, and G. Chinetti-Gbaguidi. 2012. Human adipose tissue macrophages display activation of cancer-related pathways. The Journal of Biological Chemistry 287: 21904–21913.PubMedCrossRefGoogle Scholar
  73. Mcwhirter, S.M., B.R. Tenoever, and T. Maniatis. 2005. Connecting mitochondria and innate immunity. Cell 122: 645–647.PubMedCrossRefGoogle Scholar
  74. Miller, J.C., B.D. Brown, T. Shay, E.L. Gautier, V. Jojic, A. Cohain, G. Pandey, M. Leboeuf, K.G. Elpek, J. Helft, D. Hashimoto, A. Chow, J. Price, M. Greter, M. Bogunovic, A. Bellemare-Pelletier, P.S. Frenette, G.J. Randolph, S.J. Turley, and M. Merad. 2012. Deciphering the transcriptional network of the dendritic cell lineage. Nature Immunology 13: 888–899.PubMedCrossRefGoogle Scholar
  75. Morris, D.L., K.E. Oatmen, T. Wang, J.L. Delproposto, and C.N. Lumeng. 2012. CX3CR1 deficiency does not influence trafficking of adipose tissue macrophages in mice with diet-induced obesity. Obesity (Silver Spring) 20: 1189–1199.CrossRefGoogle Scholar
  76. Mourkioti, F., P. Kratsios, T. Luedde, Y.H. Song, P. Delafontaine, R. Adami, V. Parente, R. Bottinelli, M. Pasparakis, and N. Rosenthal. 2006. Targeted ablation of IKK2 improves skeletal muscle strength, maintains mass, and promotes regeneration. The Journal of Clinical Investigation 116: 2945–2954.PubMedCrossRefGoogle Scholar
  77. Nahrendorf, M., F.K. Swirski, E. Aikawa, L. Stangenberg, T. Wurdinger, J.L. Figueiredo, P. Libby, R. Weissleder, and M.J. Pittet. 2007. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. Journal of Experimental Medicine 204: 3037–3047.PubMedCrossRefGoogle Scholar
  78. Neels, J.G., and J.M. Olefsky. 2006. Inflamed fat: What starts the fire? The Journal of Clinical Investigation 116: 33–35.PubMedCrossRefGoogle Scholar
  79. Nguyen, M.T., S. Favelyukis, A.K. Nguyen, D. Reichart, P.A. Scott, A. Jenn, R. Liu-Bryan, C.K. Glass, J.G. Neels, and J.M. Olefsky. 2007. 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. Journal of Biological Chemistry 282: 35279–35292.PubMedCrossRefGoogle Scholar
  80. Nicholls, H.T., G. Kowalski, D.J. Kennedy, S. Risis, L.A. Zaffino, N. Watson, P. Kanellakis, M.J. Watt, A. Bobik, A. Bonen, M. Febbraio, G.I. Lancaster, and M.A. Febbraio. 2011. Hematopoietic cell-restricted deletion of CD36 reduces high-fat diet-induced macrophage infiltration and improves insulin signaling in adipose tissue. Diabetes 60: 1100–1110.PubMedCrossRefGoogle Scholar
  81. Niess, J.H., S. Brand, X. Gu, L. Landsman, S. Jung, B.A. Mccormick, J.M. Vyas, M. Boes, H.L. Ploegh, J.G. Fox, D.R. Littman, and H.C. Reinecker. 2005. CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science 307: 254–258.PubMedCrossRefGoogle Scholar
  82. Nishimura, S., I. Manabe, M. Nagasaki, K. Eto, H. Yamashita, M. Ohsugi, M. Otsu, K. Hara, K. Ueki, S. Sugiura, K. Yoshimura, T. Kadowaki, and R. Nagai. 2009. CD8 + effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nature Medicine 15: 914–920.PubMedCrossRefGoogle Scholar
  83. Nomiyama, T., D. Perez-Tilve, D. Ogawa, F. Gizard, Y. Zhao, E.B. Heywood, K.L. Jones, R. Kawamori, L.A. Cassis, M.H. Tschop, and D. Bruemmer. 2007. Osteopontin mediates obesity-induced adipose tissue macrophage infiltration and insulin resistance in mice. The Journal of Clinical Investigation 117: 2877–2888.PubMedCrossRefGoogle Scholar
  84. Obstfeld, A.E., E. Sugaru, M. Thearle, A.M. Francisco, C. Gayet, H.N. Ginsberg, E.V. Ables, and A.W. Ferrante Jr. 2010. C–C chemokine receptor 2 (CCR2) regulates the hepatic recruitment of myeloid cells that promote obesity-induced hepatic steatosis. Diabetes 59: 916–925.PubMedCrossRefGoogle Scholar
  85. Odegaard, J.I., R.R. Ricardo-Gonzalez, M.H. Goforth, C.R. Morel, V. Subramanian, L. Mukundan, A.R. Eagle, D. Vats, F. Brombacher, A.W. Ferrante, and A. Chawla. 2007. Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. Nature 447: 1116–1120.PubMedCrossRefGoogle Scholar
  86. Oh, D.Y., S. Talukdar, E.J. Bae, T. Imamura, H. Morinaga, W. Fan, P. Li, W.J. Lu, S.M. Watkins, and J.M. Olefsky. 2010. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 142: 687–698.PubMedCrossRefGoogle Scholar
  87. Osborn, O., and J.M. Olefsky. 2012. The cellular and signaling networks linking the immune system and metabolism in disease. Nature Medicine 18: 363–374.PubMedCrossRefGoogle Scholar
  88. Patsouris, D., P.P. Li, D. Thapar, J. Chapman, J.M. Olefsky, and J.G. Neels. 2008. Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals. Cell Metabolism 8: 301–309.PubMedCrossRefGoogle Scholar
  89. Pickup, J.C. 2004. Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes Care 27: 813–823.PubMedCrossRefGoogle Scholar
  90. Pradhan, A.D., N.R. Cook, J.E. Buring, J.E. Manson, and P.M. Ridker. 2003. C-reactive protein is independently associated with fasting insulin in nondiabetic women. Arterioscler. Thromb. Vac. Biol. 23: 650–655.CrossRefGoogle Scholar
  91. Pradhan, A.D., J.E. Manson, N. Rifai, J.E. Buring, and P.M. Ridker. 2001. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 286: 327–334.PubMedCrossRefGoogle Scholar
  92. Prieur, X., C.Y. Mok, V.R. Velagapudi, V. Nunez, L. Fuentes, D. Montaner, K. Ishikawa, A. Camacho, N. Barbarroja, S. O’rahilly, J.K. Sethi, J. Dopazo, M. Oresic, M. Ricote, and A. Vidal-Puig. 2011. Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice. Diabetes 60: 797–809.PubMedCrossRefGoogle Scholar
  93. Razani, B., C. Feng, T. Coleman, R. Emanuel, H. Wen, S. Hwang, J.P. Ting, H.W. Virgin, M.B. Kastan, and C.F. Semenkovich. 2012. Autophagy links inflammasomes to atherosclerotic progression. Cell Metabolism 15: 534–544.PubMedCrossRefGoogle Scholar
  94. Reaven, G.M. 1988. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 37: 1595–1607.PubMedCrossRefGoogle Scholar
  95. Robker, R.L., R.G. Collins, A.L. Beaudet, H.J. Mersmann, and C.W. Smith. 2004. Leukocyte migration in adipose tissue of mice null for ICAM-1 and Mac-1 adhesion receptors. Obesity Research 12: 936–940.PubMedCrossRefGoogle Scholar
  96. Rohl, M., M. Pasparakis, S. Baudler, J. Baumgartl, D. Gautam, M. Huth, R. De Lorenzi, W. Krone, K. Rajewsky, and J.C. Bruning. 2004. Conditional disruption of IkappaB kinase 2 fails to prevent obesity-induced insulin resistance. The Journal of Clinical Investigation 113: 474–481.PubMedGoogle Scholar
  97. Romeo, G.R., J. Lee, and S.E. Shoelson. 2012. Metabolic Syndrome, Insulin Resistance, and Roles of Inflammation Mechanisms and Therapeutic Targets. Atertio. Thromb. Vasc. Biol. 32: 1771–1776.CrossRefGoogle Scholar
  98. Rosenbauer, F., and D.G. Tenen. 2007. Transcription factors in myeloid development: Balancing differentiation with transformation. Nature Reviews Immunology 7: 105–117.PubMedCrossRefGoogle Scholar
  99. Ruan, H., N. Hacohen, T.R. Golub, L. Van Parijs, and H.F. Lodish. 2002. Tumor necrosis factor-alpha suppresses adipocyte-specific genes and activates expression of preadipocyte genes in 3T3-L1 adipocytes: Nuclear factor-kappaB activation by TNF-alpha is obligatory. Diabetes 51: 1319–1336.PubMedCrossRefGoogle Scholar
  100. Saberi, M., N.B. Woods, C. De Luca, S. Schenk, J.C. Lu, G. Bandyopadhyay, I.M. Verma, and J.M. Olefsky. 2009. Hematopoietic cell-specific deletion of toll-like receptor 4 ameliorates hepatic and adipose tissue insulin resistance in high-fat-fed mice. Cell Metabolism 10: 419–429.PubMedCrossRefGoogle Scholar
  101. Sachithanandan, N., K.L. Graham, S. Galic, J.E. Honeyman, S.L. Fynch, K.A. Hewitt, G.R. Steinberg, and T.W. Kay. 2011. Macrophage deletion of SOCS1 increases sensitivity to LPS and palmitic acid and results in systemic inflammation and hepatic insulin resistance. Diabetes 60: 2023–2031.PubMedCrossRefGoogle Scholar
  102. Sadik, C.D., N.D. Kim, and A.D. Luster. 2011. Neutrophils cascading their way to inflammation. Trends in Immunology 32: 452–460.PubMedCrossRefGoogle Scholar
  103. Schmidt, M.I., B.B. Duncan, A.R. Sharrett, G. Lindberg, P.J. Savage, S. Offenbacher, M.I. Azambuja, R.P. Tracy, and G. Heiss. 1999. Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis Risk in Communities study): A cohort study. Lancet 353: 1649–1652.PubMedCrossRefGoogle Scholar
  104. Serhan, C.N., N. Chiang, and T.E. Van Dyke. 2008. Resolving inflammation: Dual anti-inflammatory and pro-resolution lipid mediators. Nature Reviews Immunology 8: 349–361.PubMedCrossRefGoogle Scholar
  105. Shi, H., M.V. Kokoeva, K. Inouye, I. Tzameli, H. Yin, and J.S. Flier. 2006. TLR4 links innate immunity and fatty acid-induced insulin resistance. The Journal of Clinical Investigation 116: 3015–3025.PubMedCrossRefGoogle Scholar
  106. Shoelson, S.E., J. Lee, and A.B. Goldfine. 2006. Inflammation and insulin resistance. The Journal of Clinical Investigation 116: 1793–1801.PubMedCrossRefGoogle Scholar
  107. Shoelson, S.E., J. Lee, and M. Yuan. 2003. Inflammation and the IKKβ/IκB/NF-κB axis in obesity- and diet-induced insulin resistance. International Journal of Obesity and Related Metabolic Disorders 27: S49–S52.PubMedCrossRefGoogle Scholar
  108. Silva, M.T. 2010. Neutrophils and macrophages work in concert as inducers and effectors of adaptive immunity against extracellular and intracellular microbial pathogens. J. Leukocyte Biol. 87: 805–813.PubMedCrossRefGoogle Scholar
  109. Soehnlein, O., and L. Lindbom. 2010. Phagocyte partnership during the onset and resolution of inflammation. Nature Reviews Immunology 10: 427–439.PubMedCrossRefGoogle Scholar
  110. Solinas, G., and M. Karin. 2010. JNK1 and IKKbeta: Molecular links between obesity and metabolic dysfunction. FASEB Journal 24: 2596–2611.PubMedCrossRefGoogle Scholar
  111. Spite, M., J. Hellmann, Y. Tang, S.P. Mathis, M. Kosuri, A. Bhatnagar, V.R. Jala, and B. Haribabu. 2011. Deficiency of the leukotriene B4 receptor, BLT-1, protects against systemic insulin resistance in diet-induced obesity. Journal of Immunology 187: 1942–1949.CrossRefGoogle Scholar
  112. Stephens, J.M., J. Lee, and P.F. Pilch. 1997. Tumor necrosis factor-alpha-induced insulin resistance in 3T3-L1 adipocytes is accompanied by a loss of insulin receptor substrate-1 and GLUT4 expression without a loss of insulin receptor-mediated signal transduction. Journal of Biological Chemistry 272: 971–976.PubMedCrossRefGoogle Scholar
  113. Stephens, J.M., and P.H. Pekala. 1992. Transcriptional repression of the C/EBP-alpha and GLUT4 genes in 3T3-L1 adipocytes by tumor necrosis factor-alpha. Regulations is coordinate and independent of protein synthesis. The Journal of biological chemistry 267: 13580–13584.PubMedGoogle Scholar
  114. Stern, M.P. 1995. Diabetes and cardiovascular disease. The “common soil” hypothesis. Diabetes 44: 369–374.PubMedCrossRefGoogle Scholar
  115. Stienstra, R., C.J. Tack, T.D. Kanneganti, L.A. Joosten, and M.G. Netea. 2012. The inflammasome puts obesity in the danger zone. Cell Metabolism 15: 10–18.PubMedCrossRefGoogle Scholar
  116. Stienstra, R., J.A. Van Diepen, C.J. Tack, M.H. Zaki, F.L. Van De Veerdonk, D. Perera, G.A. Neale, G.J. Hooiveld, A. Hijmans, I. Vroegrijk, S. Van Den Berg, J. Romijn, P.C. Rensen, L.A. Joosten, M.G. Netea, and T.D. Kanneganti. 2011. Inflammasome is a central player in the induction of obesity and insulin resistance. Proceedings of the National Academy of Sciences of the United States of America 108: 15324–15329.PubMedCrossRefGoogle Scholar
  117. Swirski, F.K., P. Libby, E. Aikawa, P. Alcaide, F.W. Luscinskas, R. Weissleder, and M.J. Pittet. 2007. Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. The Journal of Clinical Investigation 117: 195–205.PubMedCrossRefGoogle Scholar
  118. Swirski, F.K., M. Nahrendorf, M. Etzrodt, M. Wildgruber, V. Cortez-Retamozo, P. Panizzi, J.L. Figueiredo, R.H. Kohler, A. Chudnovskiy, P. Waterman, E. Aikawa, T.R. Mempel, P. Libby, R. Weissleder, and M.J. Pittet. 2009. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science 325: 612–616.PubMedCrossRefGoogle Scholar
  119. Tacke, F., D. Alvarez, T.J. Kaplan, C. Jakubzick, R. Spanbroek, J. Llodra, A. Garin, J. Liu, M. Mack, N. Van Rooijen, S.A. Lira, A.J. Habenicht, and G.J. Randolph. 2007. Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. The Journal of Clinical Investigation 117: 185–194.PubMedCrossRefGoogle Scholar
  120. Takahashi, K., S. Mizuarai, H. Araki, S. Mashiko, A. Ishihara, A. Kanatani, H. Itadani, and H. Kotani. 2003. Adiposity elevates plasma MCP-1 levels leading to the increased CD11b-positive monocytes in mice. Journal of Biological Chemistry 278: 46654–46660.PubMedCrossRefGoogle Scholar
  121. Taylor, P.R., L. Martinez-Pomares, M. Stacey, H.H. Lin, G.D. Brown, and S. Gordon. 2005. Macrophage receptors and immune recognition. Annual Review of Immunology 23: 901–944.PubMedCrossRefGoogle Scholar
  122. Tilg, H., and A.R. Moschen. 2006. Adipocytokines: Mediators linking adipose tissue, inflammation and immunity. Nature Reviews Immunology 6: 772–783.PubMedCrossRefGoogle Scholar
  123. Tripathy, D., P. Mohanty, S. Dhindsa, T. Syed, H. Ghanim, A. Aljada, and P. Dandona. 2003. Elevation of free fatty acids induces inflammation and impairs vascular reactivity in healthy subjects. Diabetes 52: 2882–2887.PubMedCrossRefGoogle Scholar
  124. Tsukumo, D.M., M.A. Carvalho-Filho, J.B. Carvalheira, P.O. Prada, S.M. Hirabara, A.A. Schenka, E.P. Araujo, J. Vassallo, R. Curi, L.A. Velloso, and M.J. Saad. 2007. Loss-of-function mutation in Toll-like receptor 4 prevents diet-induced obesity and insulin resistance. Diabetes 56: 1986–1998.PubMedCrossRefGoogle Scholar
  125. Uysal, K.T., S.M. Wiesbrock, and G.S. Hotamisligil. 1998. Functional analysis of tumor necrosis factor (TNF) receptors in TNF-alpha-mediated insulin resistance in genetic obesity. Endocrinology 139: 4832–4838.PubMedCrossRefGoogle Scholar
  126. Uysal, K.T., S.M. Wiesbrock, M.W. Marino, and G.S. Hotamisligil. 1997. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 389: 610–614.PubMedCrossRefGoogle Scholar
  127. Vandanmagsar, B., Y.H. Youm, A. Ravussin, J.E. Galgani, K. Stadler, R.L. Mynatt, E. Ravussin, J.M. Stephens, and V.D. Dixit. 2011. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nature Medicine 17: 179–188.PubMedCrossRefGoogle Scholar
  128. Vozarova, B., C. Weyer, R.S. Lindsay, R.E. Pratley, C. Bogardus, and P.A. Tataranni. 2002. High white blood cell count is associated with a worsening of insulin sensitivity and predicts the development of type 2 diabetes. Diabetes 51: 455–461.PubMedCrossRefGoogle Scholar
  129. Watanabe, Y., T. Nakamura, S. Ishikawa, S. Fujisaka, I. Usui, K. Tsuneyama, Y. Ichihara, T. Wada, Y. Hirata, T. Suganami, H. Izaki, S. Akira, K. Miyake, H.O. Kanayama, M. Shimabukuro, M. Sata, T. Sasaoka, Y. Ogawa, K. Tobe, K. Takatsu, and Y. Nagai. 2012. The radioprotective 105/MD-1 complex contributes to diet-induced obesity and adipose tissue inflammation. Diabetes 61: 1199–1209.PubMedCrossRefGoogle Scholar
  130. Weisberg, S.P., D. Hunter, R. Huber, J. Lemieux, S. Slaymaker, K. Vaddi, I. Charo, R.L. Leibel, and A.W. Ferrante Jr. 2006. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. The Journal of Clinical Investigation 116: 115–124.PubMedCrossRefGoogle Scholar
  131. Weisberg, S.P., D. Mccann, M. Desai, M. Rosenbaum, R.L. Leibel, and A.W. Ferrante Jr. 2003. Obesity is associated with macrophage accumulation in adipose tissue. The Journal of Clinical Investigation 112: 1796–1808.PubMedGoogle Scholar
  132. Wen, H., D. Gris, Y. Lei, S. Jha, L. Zhang, M.T. Huang, W.J. Brickey, and J.P. Ting. 2011. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nature Immunology 12: 408–415.PubMedCrossRefGoogle Scholar
  133. Westcott, D.J., J.B. Delproposto, L.M. Geletka, T. Wang, K. Singer, A.R. Saltiel, and C.N. Lumeng. 2009. MGL1 promotes adipose tissue inflammation and insulin resistance by regulating 7/4hi monocytes in obesity. The Journal of Experimental Medicine 206: 3143–3156.PubMedCrossRefGoogle Scholar
  134. Winer, S., Y. Chan, G. Paltser, D. Truong, H. Tsui, J. Bahrami, R. Dorfman, Y. Wang, J. Zielenski, F. Mastronardi, Y. Maezawa, D.J. Drucker, E. Engleman, D. Winer, and H.M. Dosch. 2009. Normalization of obesity-associated insulin resistance through immunotherapy. Nature Medicine 15: 921–929.PubMedCrossRefGoogle Scholar
  135. Winer, D.A., S. Winer, L. Shen, P.P. Wadia, J. Yantha, G. Paltser, H. Tsui, P. Wu, M.G. Davidson, M.N. Alonso, H.X. Leong, A. Glassford, M. Caimol, J.A. Kenkel, T.F. Tedder, T. Mclaughlin, D.B. Miklos, H.M. Dosch, and E.G. Engleman. 2011. B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nature Medicine 17: 610–617.PubMedCrossRefGoogle Scholar
  136. Xu, H., G.T. Barnes, Q. Yang, G. Tan, D. Yang, C.J. Chou, J. Sole, A. Nichols, J.S. Ross, L.A. Tartaglia, and H. Chen. 2003. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. The Journal of Clinical Investigation 112: 1821–1830.PubMedGoogle Scholar
  137. Yan, S.F., Y.S. Zou, M. Mendelsohn, Y. Gao, Y. Naka, S. Du Yan, D. Pinsky, and D. Stern. 1997. Nuclear factor interleukin 6 motifs mediate tissue-specific gene transcription in hypoxia. Journal of Biological Chemistry 272: 4287–4294.PubMedCrossRefGoogle Scholar
  138. Yuan, M., N. Konstantopoulos, J. Lee, L. Hansen, Z.W. Li, M. Karin, and S.E. Shoelson. 2001. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of IKKβ. Science 293: 1673–1677.PubMedCrossRefGoogle Scholar
  139. Yudkin, J.S., M. Kumari, S.E. Humphries, and V. Mohamed-Ali. 2000. Inflammation, obesity, stress and coronary heart disease: Is interleukin-6 the link? Atherosclerosis 148: 209–214.PubMedCrossRefGoogle Scholar
  140. Zeyda, M., D. Farmer, J. Todoric, O. Aszmann, M. Speiser, G. Gyori, G.J. Zlabinger, and T.M. Stulnig. 2007. Human adipose tissue macrophages are of an anti-inflammatory phenotype but capable of excessive pro-inflammatory mediator production. International Journal of Obesity (London) 31: 1420–1428.CrossRefGoogle Scholar
  141. Zhu, J., H. Yamane, and W.E. Paul. 2010. Differentiation of effector CD4 T cell populations. Annual Review of Immunology 28: 445–489.PubMedCrossRefGoogle Scholar
  142. Ziegler-Heitbrock, L. 2007. The CD14 + CD16 + blood monocytes: Their role in infection and inflammation. Journal of Leukocyte Biology 81: 584–592.PubMedCrossRefGoogle Scholar
  143. Ziegler-Heitbrock, H.W., G. Fingerle, M. Strobel, W. Schraut, F. Stelter, C. Schutt, B. Passlick, and A. Pforte. 1993. The novel subset of CD14 +/CD16 + blood monocytes exhibits features of tissue macrophages. European Journal of Immunology 23: 2053–2058.PubMedCrossRefGoogle Scholar

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© The Pharmaceutical Society of Korea 2013

Authors and Affiliations

  1. 1.Joslin Diabetes CenterHarvard Medical SchoolBostonUSA

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