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  • Review Article
  • Published:

Exploring the full spectrum of macrophage activation

Nature Reviews Immunology volume 8, pages 958–969 (2008)Cite this article

A Corrigendum to this article was published on 01 June 2010

Key Points

  • Macrophages exhibit remarkable plasticity, which allows them to change their physiology in response to various different environmental stimuli.

  • The physiological characterization of each of these different macrophage populations may help to explain disease aetiologies.

  • The identification of biochemical markers that are specific for each of these macrophage populations may allow us to delete specific populations of macrophages, or to diagnose disease progression or resolution by the presence or absence of these populations.

  • Three populations of activated macrophages have been identified with unique characteristics. In addition, examples from disease states are given, in which macrophages share characteristics of more than one population. This provides a conceptual framework for a large number of different macrophage subpopulations based on this simple three-cell scaffold.

  • Some pathogens can exploit these changes in macrophage physiology and use macrophages for intracellular growth.

  • During disease progression, it is probable that macrophage populations will shift their phenotype, and this shift can contribute to disease resolution or progression.

Abstract

Macrophages display remarkable plasticity and can change their physiology in response to environmental cues. These changes can give rise to different populations of cells with distinct functions. In this Review we suggest a new grouping of macrophage populations based on three different homeostatic activities — host defence, wound healing and immune regulation. We propose that similarly to primary colours, these three basic macrophage populations can blend into various other 'shades' of activation. We characterize each population and provide examples of macrophages from specific disease states that have the characteristics of one or more of these populations.

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Figure 1: Colour wheel of macrophage activation.
Figure 2: Monocyte heterogeneity.
Figure 3: Cytokines produced by immune cells can give rise to macrophages with distinct physiologies.
Figure 4: Interactions between macrophage and T cells.
Figure 5: The plasticity of activated macrophages.

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References

  1. Nathan, C. Metchnikoff's legacy in 2008. Nature Immunol. 9, 695–698 (2008).

    CAS  Google Scholar 

  2. Kono, H. & Rock, K. L. How dying cells alert the immune system to danger. Nature Rev. Immunol. 8, 279–289 (2008).

    CAS  Google Scholar 

  3. Erwig, L. P. & Henson, P. M. Immunological consequences of apoptotic cell phagocytosis. Am. J. Pathol. 171, 2–8 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Zhang, X. & Mosser, D. M. Macrophage activation by endogenous danger signals. J. Pathol. 214, 161–178 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Chen, C. J. et al. Identification of a key pathway required for the sterile inflammatory response triggered by dying cells. Nature Med. 13, 851–856 (2007).

    CAS  PubMed  Google Scholar 

  6. Park, J. S. et al. Involvement of Toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J. Biol. Chem. 279, 7370–7377 (2004).

    CAS  PubMed  Google Scholar 

  7. Mackaness, G. B. Cellular immunity and the parasite. Adv. Exp. Med. Biol. 93, 65–73 (1977).

    CAS  PubMed  Google Scholar 

  8. Gordon, S. Alternative activation of macrophages. Nature Rev. Immunol. 3, 23–35 (2003).

    CAS  Google Scholar 

  9. Martinez, F. O., Sica, A., Mantovani, A. & Locati, M. Macrophage activation and polarization. Front. Biosci. 13, 453–461 (2008). In this paper the authors proposed that the M1 and M2 designation for macrophages should be primarily based on the ratio of IL-12 to IL-10 production.

    CAS  PubMed  Google Scholar 

  10. Edwards, J. P., Zhang, X., Frauwirth, K. A. & Mosser, D. M. Biochemical and functional characterization of three activated macrophage populations. J. Leukoc. Biol. 80, 1298–1307 (2006). This work shows that alternatively activated macrophages are biochemically and functionally distinct from regulatory macrophages.

    CAS  PubMed  Google Scholar 

  11. Gordon, S. & Taylor, P. R. Monocyte and macrophage heterogeneity. Nature Rev. Immunol. 5, 953–964 (2005).

    CAS  Google Scholar 

  12. Nahrendorf, M. et al. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J. Exp. Med. 204, 3037–3047 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Sunderkotter, C. et al. Subpopulations of mouse blood monocytes differ in maturation stage and inflammatory response. J. Immunol. 172, 4410–4417 (2004).

    PubMed  Google Scholar 

  14. Geissmann, F., Jung, S. & Littman, D. R. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19, 71–82 (2003). This study shows that distinct monocyte populations exist, and have different cell-surface markers and homing capacities.

    CAS  PubMed  Google Scholar 

  15. Strauss-Ayali, D., Conrad, S. M. & Mosser, D. M. Monocyte subpopulations and their differentiation patterns during infection. J. Leukoc. Biol. 82, 244–252 (2007).

    CAS  PubMed  Google Scholar 

  16. Passlick, B., Flieger, D. & Ziegler-Heitbrock, H. W. Identification and characterization of a novel monocyte subpopulation in human peripheral blood. Blood 74, 2527–2534 (1989).

    CAS  PubMed  Google Scholar 

  17. Randolph, G. J., Inaba, K., Robbiani, D. F., Steinman, R. M. & Muller, W. A. Differentiation of phagocytic monocytes into lymph node dendritic cells in vivo. Immunity 11, 753–761 (1999).

    CAS  PubMed  Google Scholar 

  18. Auffray, C. et al. Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science 317, 666–670 (2007).

    CAS  PubMed  Google Scholar 

  19. Ajami, B., Bennett, J. L., Krieger, C., Tetzlaff, W. & Rossi, F. M. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nature Neurosci. 10, 1538–1543 (2007).

    CAS  PubMed  Google Scholar 

  20. Gordon, S. The macrophage: past, present and future. Eur. J. Immunol. 37, S9–S17 (2007).

    CAS  PubMed  Google Scholar 

  21. O'Shea, J. J. & Murray, P. J. Cytokine signaling modules in inflammatory responses. Immunity 28, 477–487 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Dale, D. C., Boxer, L. & Liles, W. C. The phagocytes: neutrophils and monocytes. Blood 112, 935–945 (2008).

    CAS  PubMed  Google Scholar 

  23. Yamamoto, M. et al. Role of adaptor TRIF in the MyD88-independent Toll-like receptor signaling pathway. Science 301, 640–643 (2003). This work shows that mice lacking the TLR adaptor molecule TRIF are defective in TLR3- and TLR4-mediated IFNγ production.

    Article  CAS  PubMed  Google Scholar 

  24. Langrish, C. L. et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201, 233–240 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Veldhoen, M., Hocking, R. J., Atkins, C. J., Locksley, R. M. & Stockinger, B. TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24, 179–189 (2006).

    CAS  PubMed  Google Scholar 

  26. Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).

    CAS  PubMed  Google Scholar 

  27. Kolls, J. K. & Linden, A. Interleukin-17 family members and inflammation. Immunity 21, 467–476 (2004).

    CAS  PubMed  Google Scholar 

  28. Fadok, V. A. et al. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-β, PGE2, and PAF. J. Clin. Invest. 101, 890–898 (1998). This work shows that the phagocytosis of apoptotic cells by macrophages is associated with the production of TGFβ, which inhibits the production of pro-inflammatory cytokines.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Filipe-Santos, O. et al. Inborn errors of IL-12/23- and IFN-γ-mediated immunity: molecular, cellular, and clinical features. Semin. Immunol. 18, 347–361 (2006).

    CAS  PubMed  Google Scholar 

  30. Nandan, D. & Reiner, N. E. Attenuation of γ interferon-induced tyrosine phosphorylation in mononuclear phagocytes infected with Leishmania donovani: selective inhibition of signaling through Janus kinases and Stat1. Infect. Immun. 63, 4495–4500 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Pai, R. K., Convery, M., Hamilton, T. A., Boom, W. H. & Harding, C. V. Inhibition of IFN-γ-induced class II transactivator expression by a 19-kDa lipoprotein from Mycobacterium tuberculosis: a potential mechanism for immune evasion. J. Immunol. 171, 175–184 (2003).

    CAS  PubMed  Google Scholar 

  32. Szekanecz, Z. & Koch, A. E. Macrophages and their products in rheumatoid arthritis. Curr. Opin. Rheumatol. 19, 289–295 (2007).

    PubMed  Google Scholar 

  33. Loke, P. et al. Alternative activation is an innate response to injury that requires CD4+ T cells to be sustained during chronic infection. J. Immunol. 179, 3926–3936 (2007). This study shows that the production of IL-4 and IL-13 is a rapid innate immune response to tissue injury.

    CAS  PubMed  Google Scholar 

  34. Brandt, E., Woerly, G., Younes, A. B., Loiseau, S. & Capron, M. IL-4 production by human polymorphonuclear neutrophils. J. Leukoc. Biol. 68, 125–130 (2000).

    CAS  PubMed  Google Scholar 

  35. Reese, T. A. et al. Chitin induces accumulation in tissue of innate immune cells associated with allergy. Nature 447, 92–96 (2007). This work demonstrates that chitin induces the production of IL-4 by eosinophils and basophils.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Kreider, T., Anthony, R. M., Urban, J. F. Jr & Gause, W. C. Alternatively activated macrophages in helminth infections. Curr. Opin. Immunol. 19, 448–453 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Stein, M., Keshav, S., Harris, N. & Gordon, S. Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation. J. Exp. Med. 176, 287–292 (1992). This is the initial observation that IL-4 upregulates the expression of macrophage mannose receptor, thereby giving rise to the term alternative activation.

    CAS  PubMed  Google Scholar 

  38. Raes, G., Beschin, A., Ghassabeh, G. H. & De, B. P. Alternatively activated macrophages in protozoan infections. Curr. Opin. Immunol. 19, 454–459 (2007).

    CAS  PubMed  Google Scholar 

  39. Wilson, M. S. et al. Immunopathology of schistosomiasis. Immunol. Cell Biol. 85, 148–154 (2007).

    CAS  PubMed  Google Scholar 

  40. Cordeiro-da-Silva, A. et al. Immunological alterations induced by polyamine derivatives on murine splenocytes and human mononuclear cells. Int. Immunopharmacol. 4, 547–556 (2004).

    CAS  PubMed  Google Scholar 

  41. Anthony, R. M. et al. Memory TH2 cells induce alternatively activated macrophages to mediate protection against nematode parasites. Nature Med. 12, 955–960 (2006).

    CAS  PubMed  Google Scholar 

  42. Zhao, A. et al. Th2 cytokine-induced alterations in intestinal smooth muscle function depend on alternatively activated macrophages. Gastroenterology 135, 217–225 (2008).

    CAS  PubMed  Google Scholar 

  43. Raes, G. et al. Differential expression of FIZZ1 and Ym1 in alternatively versus classically activated macrophages. J. Leukoc. Biol. 71, 597–602 (2002).

    CAS  PubMed  Google Scholar 

  44. Kzhyshkowska, J. et al. Novel stabilin-1 interacting chitinase-like protein (SI-CLP) is up-regulated in alternatively activated macrophages and secreted via lysosomal pathway. Blood 107, 3221–3228 (2006).

    CAS  PubMed  Google Scholar 

  45. Zhu, Z. et al. Acidic mammalian chitinase in asthmatic Th2 inflammation and IL-13 pathway activation. Science 304, 1678–1682 (2004).

    CAS  PubMed  Google Scholar 

  46. Bleau, G., Massicotte, F., Merlen, Y. & Boisvert, C. Mammalian chitinase-like proteins. EXS 87, 211–221 (1999).

    CAS  PubMed  Google Scholar 

  47. Fusetti, F. et al. Structure of human chitotriosidase. Implications for specific inhibitor design and function of mammalian chitinase-like lectins. J. Biol. Chem. 277, 25537–25544 (2002).

    CAS  PubMed  Google Scholar 

  48. Hesse, M. et al. Differential regulation of nitric oxide synthase-2 and arginase-1 by type 1/type 2 cytokines in vivo: granulomatous pathology is shaped by the pattern of L-arginine metabolism. J. Immunol. 167, 6533–6544 (2001). This study shows that arginase-1 production by alternatively activated macrophages depends on T H 2-type cytokines and inversely correlates with nitric oxide production.

    CAS  PubMed  Google Scholar 

  49. Munitz, A., Brandt, E. B., Mingler, M., Finkelman, F. D. & Rothenberg, M. E. Distinct roles for IL-13 and IL-4 via IL-13 receptor α1 and the type II IL-4 receptor in asthma pathogenesis. Proc. Natl Acad. Sci. USA 105, 7240–7245 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Harris, J. et al. T helper 2 cytokines inhibit autophagic control of intracellular Mycobacterium tuberculosis. Immunity 27, 505–517 (2007).

    CAS  PubMed  Google Scholar 

  51. Kropf, P. et al. Arginase and polyamine synthesis are key factors in the regulation of experimental leishmaniasis in vivo. FASEB J. 19, 1000–1002 (2005).

    CAS  PubMed  Google Scholar 

  52. Muller, U. et al. IL-13 induces disease-promoting type 2 cytokines, alternatively activated macrophages and allergic inflammation during pulmonary infection of mice with Cryptococcus neoformans. J. Immunol. 179, 5367–5377 (2007).

    PubMed  Google Scholar 

  53. Shirey, K. A., Cole, L. E., Keegan, A. D. & Vogel, S. N. Francisella tularensis live vaccine strain induces macrophage alternative activation as a survival mechanism. J. Immunol. 181, 4159–4167 (2008).

    CAS  PubMed  Google Scholar 

  54. Tumitan, A. R., Monnazzi, L. G., Ghiraldi, F. R., Cilli, E. M. & hado de Medeiros, B. M. Pattern of macrophage activation in Yersinia-resistant and Yersinia-susceptible strains of mice. Microbiol. Immunol. 51, 1021–1028 (2007).

    CAS  PubMed  Google Scholar 

  55. Sternberg, E. M. Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens. Nature Rev. Immunol. 6, 318–328 (2006).

    CAS  Google Scholar 

  56. Elenkov, I. J. Glucocorticoids and the Th1/Th2 balance. Ann. N. Y. Acad. Sci. 1024, 138–146 (2004).

    CAS  PubMed  Google Scholar 

  57. Liu, Y. et al. Glucocorticoids promote nonphlogistic phagocytosis of apoptotic leukocytes. J. Immunol. 162, 3639–3646 (1999).

    CAS  PubMed  Google Scholar 

  58. Franchimont, D. Overview of the actions of glucocorticoids on the immune response: a good model to characterize new pathways of immunosuppression for new treatment strategies. Ann. NY Acad. Sci. 1024, 124–137 (2004).

    CAS  PubMed  Google Scholar 

  59. Mosser, D. M. The many faces of macrophage activation. J. Leukoc. Biol. 73, 209–212 (2003).

    CAS  PubMed  Google Scholar 

  60. Lucas, M., Zhang, X., Prasanna, V. & Mosser, D. M. ERK activation following macrophage FcγR ligation leads to chromatin modifications at the IL-10 locus. J. Immunol. 175, 469–477 (2005). This paper shows that activation of ERK is required for the hypersecretion of IL-10 by regulatory macrophages.

    CAS  PubMed  Google Scholar 

  61. Gerber, J. S. & Mosser, D. M. Reversing lipopolysaccharide toxicity by ligating the macrophage Fcγ receptors. J. Immunol. 166, 6861–6868 (2001).

    CAS  PubMed  Google Scholar 

  62. Strassmann, G., Patil-Koota, V., Finkelman, F., Fong, M. & Kambayashi, T. Evidence for the involvement of interleukin 10 in the differential deactivation of murine peritoneal macrophages by prostaglandin E2. J. Exp. Med. 180, 2365–2370 (1994).

    CAS  PubMed  Google Scholar 

  63. Hasko, G., Pacher, P., Deitch, E. A. & Vizi, E. S. Shaping of monocyte and macrophage function by adenosine receptors. Pharmacol. Ther. 113, 264–275 (2007).

    CAS  PubMed  Google Scholar 

  64. Hasko, G., Szabo, C., Nemeth, Z. H. & Deitch, E. A. Dopamine suppresses IL-12 p40 production by lipopolysaccharide-stimulated macrophages via a β-adrenoceptor-mediated mechanism. J. Neuroimmunol. 122, 34–39 (2002).

    CAS  PubMed  Google Scholar 

  65. Sirois, J., Menard, G., Moses, A. S. & Bissonnette, E. Y. Importance of histamine in the cytokine network in the lung through H2 and H3 receptors: stimulation of IL-10 production. J. Immunol. 164, 2964–2970 (2000).

    CAS  PubMed  Google Scholar 

  66. Weigert, A. et al. Tumor cell apoptosis polarizes macrophages role of sphingosine-1-phosphate. Mol. Biol. Cell 18, 3810–3819 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Lam, C. W., Perretti, M. & Getting, S. J. Melanocortin receptor signaling in RAW264.7 macrophage cell line. Peptides 27, 404–412 (2006).

    CAS  PubMed  Google Scholar 

  68. Delgado, M., Munoz-Elias, E. J., Gomariz, R. P. & Ganea, D. Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide enhance IL-10 production by murine macrophages: in vitro and in vivo studies. J. Immunol. 162, 1707–1716 (1999).

    CAS  PubMed  Google Scholar 

  69. Huang, H., Park, P. H., McMullen, M. R. & Nagy, L. E. Mechanisms for the anti-inflammatory effects of adiponectin in macrophages. J. Gastroenterol. Hepatol. 1, S50–S53 (2008).

    Google Scholar 

  70. Ando, M., Tu, W., Nishijima, K. & Iijima, S. Siglec-9 enhances IL-10 production in macrophages via tyrosine-based motifs. Biochem. Biophys. Res. Commun. 369, 878–883 (2008).

    CAS  PubMed  Google Scholar 

  71. Biswas, S. K. et al. A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-κB and enhanced IRF-3/STAT1 activation). Blood 107, 2112–2122 (2006). In this study, tumour-associated macrophages are profiled by microarray analysis.

    CAS  PubMed  Google Scholar 

  72. Miles, S. A., Conrad, S. M., Alves, R. G., Jeronimo, S. M. & Mosser, D. M. A role for IgG immune complexes during infection with the intracellular pathogen Leishmania. J. Exp. Med. 201, 747–754 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Baetselier, P. D. et al. Alternative versus classical macrophage activation during experimental African trypanosomosis. Int. J. Parasitol. 31, 575–587 (2001).

    CAS  PubMed  Google Scholar 

  74. Kim, C. et al. Antiinflammatory cAMP signaling and cell migration genes co-opted by the anthrax bacillus. Proc. Natl Acad. Sci. USA 105, 6150–6155 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Agrawal, A. & Pulendran, B. Anthrax lethal toxin: a weapon of multisystem destruction. Cell Mol. Life Sci. 61, 2859–2865 (2004).

    CAS  PubMed  Google Scholar 

  76. Benoit, M., Barbarat, B., Bernard, A., Olive, D. & Mege, J. L. Coxiella burnetii, the agent of Q fever, stimulates an atypical M2 activation program in human macrophages. Eur. J. Immunol. 38, 1065–1070 (2008).

    CAS  PubMed  Google Scholar 

  77. Mahalingam, S. & Lidbury, B. A. Suppression of lipopolysaccharide-induced antiviral transcription factor (STAT-1 and NF-κB) complexes by antibody-dependent enhancement of macrophage infection by Ross River virus. Proc. Natl Acad. Sci. USA 99, 13819–13824 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Stout, R. D. et al. Macrophages sequentially change their functional phenotype in response to changes in microenvironmental influences. J. Immunol. 175, 342–349 (2005).

    CAS  PubMed  Google Scholar 

  79. Klimp, A. H., de Vries, E. G., Scherphof, G. L. & Daemen, T. A potential role of macrophage activation in the treatment of cancer. Crit. Rev. Oncol. Hematol. 44, 143–161 (2002).

    CAS  PubMed  Google Scholar 

  80. Teng, M. W., Swann, J. B., Koebel, C. M., Schreiber, R. D. & Smyth, M. J. Immune-mediated dormancy: an equilibrium with cancer. J. Leukoc. Biol. 84, 988–993 (2008).

    CAS  PubMed  Google Scholar 

  81. Lin, E. Y. & Pollard, J. W. Tumor-associated macrophages press the angiogenic switch in breast cancer. Cancer Res. 67, 5064–5066 (2007). This work correlates macrophage recruitment into tumours with an angiogenic switch and a poor prognosis.

    CAS  PubMed  Google Scholar 

  82. Swann, J. B. et al. Demonstration of inflammation-induced cancer and cancer immunoediting during primary tumorigenesis. Proc. Natl Acad. Sci. USA 105, 652–656 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Romieu-Mourez, R. et al. Distinct roles for IFN regulatory factor (IRF)-3 and IRF-7 in the activation of antitumor properties of human macrophages. Cancer Res. 66, 10576–10585 (2006).

    CAS  PubMed  Google Scholar 

  84. Pollard, J. W. Macrophages define the invasive microenvironment in breast cancer. J. Leukoc. Biol. 84, 623–630 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Liu, C. H. et al. Overexpression of cyclooxygenase-2 is sufficient to induce tumorigenesis in transgenic mice. J. Biol. Chem. 276, 18563–18569 (2001).

    CAS  PubMed  Google Scholar 

  86. Knowles, H. J. & Harris, A. L. Hypoxia and oxidative stress in breast cancer. Hypoxia and tumourigenesis. Breast Cancer Res. 3, 318–322 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Kuang, D. M. et al. Tumor-derived hyaluronan induces formation of immunosuppressive macrophages through transient early activation of monocytes. Blood 110, 587–595 (2007).

    CAS  PubMed  Google Scholar 

  88. de Visser, K. E., Korets, L. V. & Coussens, L. M. De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell 7, 411–423 (2005).

    CAS  PubMed  Google Scholar 

  89. Hagemann, T. et al. “Re-educating” tumor-associated macrophages by targeting NF-κB. J. Exp. Med. 205, 1261–1268 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Lin, E. Y. et al. Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res. 66, 11238–11246 (2006).

    CAS  PubMed  Google Scholar 

  91. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Straus, D. S. & Glass, C. K. Anti-inflammatory actions of PPAR ligands: new insights on cellular and molecular mechanisms. Trends Immunol. 28, 551–558 (2007).

    CAS  PubMed  Google Scholar 

  93. Heilbronn, L. K. & Campbell, L. V. Adipose tissue macrophages, low grade inflammation and insulin resistance in human obesity. Curr. Pharm. Des. 14, 1225–1230 (2008).

    CAS  PubMed  Google Scholar 

  94. Zeyda, M. & Stulnig, T. M. Adipose tissue macrophages. Immunol. Lett. 112, 61–67 (2007).

    CAS  PubMed  Google Scholar 

  95. Cinti, S. et al. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J. Lipid Res. 46, 2347–2355 (2005).

    CAS  PubMed  Google Scholar 

  96. Bastard, J. P. et al. Recent advances in the relationship between obesity, inflammation, and insulin resistance. Eur. Cytokine Netw. 17, 4–12 (2006).

    CAS  PubMed  Google Scholar 

  97. Hansson, G. K., Robertson, A. K. & Soderberg-Naucler, C. Inflammation and atherosclerosis. Annu. Rev. Pathol. 1, 297–329 (2006).

    CAS  PubMed  Google Scholar 

  98. Fernandez, A. Z. Peroxisome proliferator-activated receptors in the modulation of the immune/inflammatory response in atherosclerosis. PPAR Res. 2008, 285842 (2008).

    PubMed  PubMed Central  Google Scholar 

  99. Martin-Fuentes, P. et al. Individual variation of scavenger receptor expression in human macrophages with oxidized low-density lipoprotein is associated with a differential inflammatory response. J. Immunol. 179, 3242–3248 (2007).

    CAS  PubMed  Google Scholar 

  100. Haque, S., Mirjafari, H. & Bruce, I. N. Atherosclerosis in rheumatoid arthritis and systemic lupus erythematosus. Curr. Opin. Lipidol. 19, 338–343 (2008).

    CAS  PubMed  Google Scholar 

  101. Roark, C. L., Simonian, P. L., Fontenot, A. P., Born, W. K. & O'Brien, R. L. γδ T cells: an important source of IL-17. Curr. Opin. Immunol. 20, 353–357 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Mangan, P. R. et al. Transforming growth factor-β induces development of the TH17 lineage. Nature 441, 231–234 (2006).

    CAS  PubMed  Google Scholar 

  103. costa-Rodriguez, E. V., Napolitani, G., Lanzavecchia, A. & Sallusto, F. Interleukins 1β and 6 but not transforming growth factor-β are essential for the differentiation of interleukin 17-producing human T helper cells. Nature Immunol. 8, 942–949 (2007).

    Google Scholar 

  104. Denning, T. L., Wang, Y. C., Patel, S. R., Williams, I. R. & Pulendran, B. Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses. Nature Immunol. 8, 1086–1094 (2007).

    CAS  Google Scholar 

  105. Jovanovic, D. V. et al. IL-17 stimulates the production and expression of proinflammatory cytokines, IL-β and TNF-α, by human macrophages. J. Immunol. 160, 3513–3521 (1998).

    CAS  PubMed  Google Scholar 

  106. Sato, K. et al. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J. Exp. Med. 203, 2673–2682 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Trinchieri, G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nature Rev. Immunol. 3, 133–146 (2003).

    CAS  Google Scholar 

  108. MacMicking, J., Xie, Q. W. & Nathan, C. Nitric oxide and macrophage function. Annu. Rev. Immunol. 15, 323–350 (1997).

    CAS  PubMed  Google Scholar 

  109. Martinez, F. O., Gordon, S., Locati, M. & Mantovani, A. Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: new molecules and patterns of gene expression. J. Immunol. 177, 7303–7311 (2006).

    CAS  PubMed  Google Scholar 

  110. Kodelja, V. et al. Alternative macrophage activation-associated CC-chemokine-1, a novel structural homologue of macrophage inflammatory protein-1 α with a Th2-associated expression pattern. J. Immunol. 160, 1411–1418 (1998).

    CAS  PubMed  Google Scholar 

  111. Raes, G. et al. FIZZ1 and Ym as tools to discriminate between differentially activated macrophages. Dev. Immunol. 9, 151–159 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Wirnsberger, G., Hebenstreit, D., Posselt, G., Horejs-Hoeck, J. & Duschl, A. IL-4 induces expression of TARC/CCL17 via two STAT6 binding sites. Eur. J. Immunol. 36, 1882–1891 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Ruckerl, D., Hessmann, M., Yoshimoto, T., Ehlers, S. & Holscher, C. Alternatively activated macrophages express the IL-27 receptor α chain WSX-1. Immunobiology 211, 427–436 (2006).

    PubMed  Google Scholar 

  114. Wynes, M. W. & Riches, D. W. Induction of macrophage insulin-like growth factor-I expression by the Th2 cytokines IL-4 and IL-13. J. Immunol. 171, 3550–3559 (2003).

    CAS  PubMed  Google Scholar 

  115. Mantovani, A., Sozzani, S., Locati, M., Allavena, P. & Sica, A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 23, 549–555 (2002).

    CAS  PubMed  Google Scholar 

  116. Goerdt, S. & Orfanos, C. E. Other functions, other genes: alternative activation of antigen presenting cells. Immunity 10, 137–142 (1999).

    CAS  PubMed  Google Scholar 

  117. Torocsik, D., Bardos, H., Nagy, L. & Adany, R. Identification of factor XIII-A as a marker of alternative macrophage activation. Cell. Mol. Life Sci. 62, 2132–2139 (2005).

    CAS  PubMed  Google Scholar 

  118. Sironi, M. et al. Differential regulation of chemokine production by Fcγ receptor engagement in human monocytes: association of CCL1 with a distinct form of M2 monocyte activation (M2b, Type 2). J. Leukoc. Biol. 80, 342–349 (2006).

    CAS  PubMed  Google Scholar 

  119. Stumhofer, J. S. & Hunter, C. A. Advances in understanding the anti-inflammatory properties of IL-27. Immunol. Lett. 117, 123–130 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work is supported in part by National Institutes of Health grants AI49388 and AI55576.

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  1. Department of Cell Biology and Molecular Genetics and the Maryland Pathogen Research Institute, University of Maryland, College Park, 20742, Maryland, USA

    David M. Mosser & Justin P. Edwards

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  1. David M. Mosser
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Correspondence to David M. Mosser.

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Glossary

Apoptosis

A common form of cell death (also known as programmed cell death) that can be caused by many physiological and developmental stimuli. Apoptosis involves cell shrinkage, chromatin condensation in the periphery of the nucleus, cell-membrane blebbing and DNA fragmentation into multiples of ∼180 base pairs. Eventually, the cell breaks up into many membrane-bound apoptotic bodies, which are phagocytosed by neighbouring cells.

Necrosis

A form of cell death that frequently results from toxic injury, hypoxia or stress. Necrosis involves the loss of cell integrity and the release of cell contents into the interstitium. This form of cell death usually occurs together with inflammation. Depending on the context, the self antigens that are released by necrotic cells could become immunogenic.

Extracellular matrix

Secreted products of many cell types that form an organized scaffold for cell support.

Classically activated macrophage

A macrophage that is activated through Toll-like receptors and interferon-γ. These cells exhibit enhanced killing of intracellular microorganisms, increased secretion of cytokines and mediators, and higher expression of co-stimulatory molecules.

Alternatively activated macrophage

A macrophage that is activated by interleukin-4 (IL-4) or IL-13 and expresses arginase-1, mannose receptor (CD206) and IL-4 receptor-α. Pathogen-associated molecular patterns that are expressed by helminths may also drive the alternative activation of macrophages.

Superoxide anions

Anions that are produced by NADPH oxidase in phagocytes and can dismutate to hydrogen peroxide, which can be converted into ferryl or hydroxyl radicals by the Fenton reaction.

Osteoclastogenesis

A process whereby haematopoietic stem cells differentiate into multinucleated osteoclasts with bone-resorbing activity.

Chitinase

An enzyme that breaks down the glycosidic bonds in chitin.

Autophagy

An evolutionarily conserved process during which acidic double-membrane vacuoles sequester intracellular contents (such as damaged organelles and macromolecules) and target them for degradation through fusion to secondary lysosomes.

Hypothalamic–pituitary–adrenal axis

A major part of the neuroendocrine system, which controls reactions to stress and regulates digestion, energy use, sexuality and the immune system (generally through an immunosuppressive action).

Glucocorticoids

A group of compounds that belongs to the corticosteroid family. These compounds can be naturally produced (hormones) or can be synthetic. They affect metabolism and have anti-inflammatory and immunosuppressive effects. Some synthetic glucocorticoids (for example, dexamethasone) are used as chemotherapeutic drugs.

Immune complexes

Antigen–antibody complexes that bind to and crosslink Fcγ receptors.

Prostaglandins

Lipid mediators that are derived from arachidonic acid through the cyclooxygenase pathway. Bergstrom, Samuelsson and Vane won the Nobel prize in Medicine in 1982 for showing that aspirin-like compounds could inhibit prostaglandin synthesis.

G-protein-coupled receptor

A receptor that is composed of seven membrane-spanning helical segments, which are connected by extracellular and intracellular loops. These receptors associate with G proteins, which are a family of trimeric intracellular-signalling proteins that have specific β- and γ-chains, and one of several α-achains.

Tumour-associated macrophage

A cell that differentiates from circulating blood monocytes that have infiltrated tumours. Tumour-associated macrophages constitute an important component of the tumour microenvironment and can have positive or negative effects on tumorigenesis (that is, tumour promotion or immunosurveillance, respectively).

Antibody-dependent enhancement

A phenomenon that was originally described in Dengue virus infection in which the presence of antibody enhances viral infection and increases disease severity.

Neoplasia

New growths or tumours, which can be either benign or malignant. Derived from the Greek for new formations.

Angiogenesis

The development of new blood vessels from existing ones. Angiogenesis is frequently associated with tumour development and metastasis.

Adipose tissue

Loose connective tissue consisting primarily of adipocytes, the major function of which is to store energy in the form of fat.

Insulin resistance

Failure of cells to appropriately respond to insulin-mediated induction of glucose uptake, resulting in increased blood sugar levels and possibly type 2 diabetes.

Metabolic syndrome

A combination of disorders, including hypertension, obesity, high blood glucose levels and dyslipidaemia, that can result in cardiovascular disease.

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Mosser, D., Edwards, J. Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8, 958–969 (2008). https://doi.org/10.1038/nri2448

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