Inflammation Research

, Volume 62, Issue 9, pp 835–843 | Cite as

Macrophages: plastic solutions to environmental heterogeneity

  • Selma GiorgioEmail author



Macrophages are among the oldest cell types in the animal kingdom, and they have a long evolutionary history and experience various evolutionary pressures. It was clear from the earliest studies that variations exist in macrophage populations. Macrophages are known to adapt to their microenvironment. Although the paradigm for macrophage plasticity is their flexible program driven by environmental signals, the most common working hypothesis is that of a dichotomy between two major macrophage phenotypes, M1 and M2.


A PubMed and Web of Science databases search was performed providing evidences that numerous authors have expanded the concept of plasticity and conducted experimental studies focusing on the complex program of phenotypes.

Results and Conclusions

This review evaluated a number of issues relating to macrophage plasticity, environmental heterogeneity and the potential for changes to be reversal or non reversal in an ecological context. The ecological principles of phenotypic plasticity which can assist in evaluating and interpreting macrophage experimental data are discussed as well.


Macrophages Mononuclear phagocyte Plasticity Reaction norm Phenotype 



This study was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo e Conselho Nacional de Desenvolvimento Cientifico e Tecnológico, Brasil. The author would like to thank Dr. O. Augusto for her suggestions and Dr. D. Kosminsky for her assistance with the figures.


  1. 1.
    Ottaviani E, Franceschi C. The invertebrate phagocytic immunocyte: clues to a common evolution of immune and neuroendocrine systems. Immunol Today. 1997;18:169–74.PubMedCrossRefGoogle Scholar
  2. 2.
    Ottaviani E, Malagoli D, Grimaldi A, De Eguileor M. The case of the “serfdom” condition of phagocytic immune cells. Invert Surv J. 2012;9:134–8.Google Scholar
  3. 3.
    Desjardins M, Houde M, Gagnon E. Phagocytosis: the convoluted way from nutrition to adaptaive immunity. Immunol Rev. 2005;207:158–65.PubMedCrossRefGoogle Scholar
  4. 4.
    Aderem A, Underhill DM. Mechanisms of phagocytosis in macrophages. Annu Rev Immunol. 1999;17:593–623.PubMedCrossRefGoogle Scholar
  5. 5.
    Dale DC, Boxer L, Liles WC. The phagocytes: neutrophils and monocytes. Blood. 2008;112:935–45.PubMedCrossRefGoogle Scholar
  6. 6.
    Metchnikoff E. Lectures on the comparative pathology of inflammation. London: Trench; 1893.Google Scholar
  7. 7.
    Silverstein AM. A history of immunology. San Diego: Academic; 1989. p. 40–56.Google Scholar
  8. 8.
    Hume DA, Ross IL, Himes SR, Sasmono RT, Wells CA, Ravasi T. The mononuclear phagocyte system revisited. J Leukoc Biol. 2002;72:621–7.PubMedGoogle Scholar
  9. 9.
    Habicht GS. Primordial immunity: foundations for the vertebrate immune system. In: Beck C, Habicht GS, Cooper EL, Marchalonis JJ, editors. The vertebrate immune system, New York: New York Academy of Sciences; 1994. pp. ix–xi.Google Scholar
  10. 10.
    Maurya MR, Benner C, Pradervand S, Glass C, Subramaniam S. Systems biology of macrophages. Adv Exp Med Biol. 2007;598:62–79.PubMedCrossRefGoogle Scholar
  11. 11.
    Germain RN, Meier-Schellersheim M, Nita-Lazar A, Fraser ID. Systems biology in immunology: a computational modeling perspective. Annu Rev Immunol. 2011;29:527–85.PubMedCrossRefGoogle Scholar
  12. 12.
    Murray PJ, Wynn TA. Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol. 2011;11:723–37.PubMedCrossRefGoogle Scholar
  13. 13.
    Halmilton JA. Therapeutic potential of targeting inflammation. Inflamm Res. 2013;62:653–65.CrossRefGoogle Scholar
  14. 14.
    Gordon S, Martinez FO. Alternative activation of macrophages: mechanism and functions. Immunity. 2010;32:593–604.PubMedCrossRefGoogle Scholar
  15. 15.
    Martinez FO, Helming L, Gordon S. Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol. 2009;27:451–83.PubMedCrossRefGoogle Scholar
  16. 16.
    Stout RD, Watkins SK, Suttles J. Functional plasticity of macrophages: in situ reprogramming of tumor-associated macrophages. J Leukoc Biol. 2009;86:1105–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8:958–69.PubMedCrossRefGoogle Scholar
  18. 18.
    Galli SJ, Borregaard N, Wynn TA. Phenotypic and functional plasticity of cells of innate immunity: macrophages, mast cells and neutrophils. Nat Immunol. 2011;12:1035–44.PubMedCrossRefGoogle Scholar
  19. 19.
    Weidenbusch M, Anders H-J. Tissue microenvironments define and get reinforced by macrophage phenotypes in homeostasis or during inflammation, repair and fibrosis. J Innate Immun. 2012;4:463–77.PubMedCrossRefGoogle Scholar
  20. 20.
    Hamilton TA. Molecular basis of macrophage activation: from gene expression to phenotypic diversity. In: Burke B, Lewis CE, editors. The macrophage. New York: Oxford University Press; 2002. p. 74–102.Google Scholar
  21. 21.
    Grage-Griebenow E, Flad HD, Ernst M. Heterogeneity of human peripheral blood monocyte subsets. J Leukoc Biol. 2001;69:11–20.PubMedGoogle Scholar
  22. 22.
    Erwig LP, Kluth DC, Rees AJ. Macrophage heterogeneity in renal inflammation. Nephrol Dial Transplant. 2003;18:1962–5.PubMedCrossRefGoogle Scholar
  23. 23.
    Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol. 2005;5:953–64.PubMedCrossRefGoogle Scholar
  24. 24.
    Kono H, Fujii H, Asakawa M, Yamamoto M, Maki A, Matsuda M, et al. Functional heterogeneity of the Kupffer cell population is involved in the mechanism of gadolinium chloride in rats administered endotoxin. J Surg Res. 2002;106:179–87.PubMedCrossRefGoogle Scholar
  25. 25.
    He Y, Sadahiro T, Noh SI, Wang H, Todo T, Chai NN. Flow cytometric isolation and phenotypic characterization of two subsets of ED2(+) (CD163) hepatic macrophages in rats. Hepatol Res. 2009;39:1208–18.PubMedCrossRefGoogle Scholar
  26. 26.
    Kinoshita M, Uchida T, Sato A, Nakashima M, Nakashima H, Shono S, et al. Characterization of two F4/80-positive Kupffer cell subsets by their function and phenotype in mice. J Hepatol. 2010;53:903–10.PubMedCrossRefGoogle Scholar
  27. 27.
    Movita D, Kreefft K, Biesta P, van Oudenaren A, Leenen PJ, Janssen HL, et al. Kupffer cells express a unique combination of phenotypic and functional characteristics compared with splenic and peritoneal macrophages. J Leukoc Biol. 2012;92:723–33.PubMedCrossRefGoogle Scholar
  28. 28.
    Kraal G. Cells in the marginal zone of the spleen. Int Rev Cytol. 1992;132:31–74.PubMedCrossRefGoogle Scholar
  29. 29.
    den Haan JM, Kraal G. Innate immune functions of macrophage subpopulations in the spleen. J Innate Immun. 2012;4:437–45.CrossRefGoogle Scholar
  30. 30.
    Gordon S. Innate immune functions of macrophages in different tissue environments. J Innate Immun. 2012;4:409–10.PubMedCrossRefGoogle Scholar
  31. 31.
    Taylor PR, Martinez-Pomares L, Stacey M, Lin HH, Brown GD, Gordon S. Macrophage receptors and immune recognition. Annu Rev Immunol. 2005;23:901–44.PubMedCrossRefGoogle Scholar
  32. 32.
    Liddiard K, Rosas M, Davies LC, Jones SA, Taylor PR. Macrophage heterogeneity and acute inflammation. Eur J Immunol. 2011;41:2503–8.PubMedCrossRefGoogle Scholar
  33. 33.
    Hashimoto D, Miller J, Merad M. Dendritic cell and macrophage heterogeneity in vivo. Immunity. 2011;35:323–35.PubMedCrossRefGoogle Scholar
  34. 34.
    Rutherford MS, Witsel A, Schook LB. Mechanisms generating functionally heterogeneous macrophages: chaos revisited. J Leukoc Biol. 1993;53:602–18.PubMedGoogle Scholar
  35. 35.
    Schust DJ, Magamatsu T. Does the classical M1/M2 dichotomy reflect the functional phenotypes of human decidual macrophages? Expert Rev Obstr Gynecol. 2011;4:377–80.CrossRefGoogle Scholar
  36. 36.
    Porcheray F, Viaud S, Rimaniol AC, Léone C, Samah B, Dereuddre-Bosquet N, et al. Macrophage activation switching: an asset for the resolution of inflammation. Clin Exp Immunol. 2005;142:481–9.PubMedGoogle Scholar
  37. 37.
    Mantovani A. Macrophage diversity and polarization: in vivo veritas. Blood. 2006;108:408–9.CrossRefGoogle Scholar
  38. 38.
    Biswas SK, Chittezhath M, Shalova IN, Lim JY. Macrophage polarization and plasticity in health and disease. Immunol Res. 2012;53:11–24.PubMedCrossRefGoogle Scholar
  39. 39.
    Daley JM, Reichner JS, Mahoney EJ, Manfield L, Henry WL Jr, Mastrofrancesco B, et al. Modulation of macrophage phenotype by soluble product(s) released from neutrophils. J Immunol. 2005;174:2265–72.PubMedGoogle Scholar
  40. 40.
    Adamson S, Leitinger N. Phenotypic modulation of macrophages in response to plaque lipids. Curr Opin Lipidol. 2011;22:335–42.PubMedCrossRefGoogle Scholar
  41. 41.
    Gleissner CA. Macrophage phenotype modulation by CXCL4 in atherosclerosis. Front Physiol. 2012;3:1.PubMedCrossRefGoogle Scholar
  42. 42.
    Gratchev A, Schledzewski K, Guillot P, Goerdt S. Alternatively activated antigen-presenting cells: molecular repertoire, immune regulation, and healing. Skin Pharmacol Appl Skin Physiol. 2001;14:272–9.PubMedCrossRefGoogle Scholar
  43. 43.
    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. 2002;23:549–55.PubMedCrossRefGoogle Scholar
  44. 44.
    Stein BE, Burr D, Constantinidis C, Laurienti PJ, Alex MM, Perrault TJ, et al. Semantic confusion regarding the development of multisensory integration: a practical solution. Eur J Neurosci. 2010;31:1713–20.PubMedCrossRefGoogle Scholar
  45. 45.
    Huang H, Fletcher A, Niu Y, Wang TY, Yu L. Characterization of lipopolysaccharide-stimulated cytokine expression in macrophages and monocytes. Inflamm Res. 2012;61:1329–38.PubMedCrossRefGoogle Scholar
  46. 46.
    ZhangW XuW, Xiong S. Blockade of Notch1 signaling alleviates murine lupus via blunting macrophage activation and M2b polarization. J Immunol. 2010;184:6465–78.CrossRefGoogle Scholar
  47. 47.
    Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004;25:677–86.PubMedCrossRefGoogle Scholar
  48. 48.
    Stout RD, Jiang C, Matta B, Tietzel I, Watkins SK, Suttles J. Macrophages sequentially change their functional phenotype in response to changes in microenvironmental influences. J Immunol. 2005;175:342–9.PubMedGoogle Scholar
  49. 49.
    Stout RD, Suttles J. Functional plasticity of macrophages: reversible adaptation to changing microenvironments. J Leukoc Biol. 2004;76:509–13.PubMedCrossRefGoogle Scholar
  50. 50.
    Stout RD, Suttles J. Immunosenescence and macrophage functional plasticity: dysregulation of macrophage function by age-associated microenvironmental changes. Immunol Rev. 2005;205:60–71.PubMedCrossRefGoogle Scholar
  51. 51.
    Stout RD. Macrophage functional phenotypes: no alternatives in dermal wound healing? J Leukoc Biol. 2010;87:19–21.PubMedCrossRefGoogle Scholar
  52. 52.
    Mills CD, Kincaid K, Alt JM, Heilman MJ, Hill AM. M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol. 2000;164:6166–73.PubMedGoogle Scholar
  53. 53.
    Meyer M, Huaux F, Gavilanes X, van den Brûle S, Lebecque P, Lore S, et al. Azithromycin reduces exaggerated cytokine production by M1 alveolar macrophages in cystic fibrosis. Am J Respir Cell Mol Biol. 2009;41:590–602.PubMedCrossRefGoogle Scholar
  54. 54.
    Ortega MT, Xie L, Mora S, Chapes SK. Evaluation of macrophage plasticity in brown and white adipose tissue. Cell Immunol. 2011;271:124–33.PubMedCrossRefGoogle Scholar
  55. 55.
    Empey KM, Orend JG, Peebles RS Jr, Egaña L, Norris KA, Oury TD, et al. Stimulation of immature lung macrophages with intranasal interferon gamma in a novel neonatal mouse model of respiratory syncytial virus infection. PLoS ONE. 2012;7:e40499.PubMedCrossRefGoogle Scholar
  56. 56.
    Colhone MC, Arrais-Silva WW, Picolli C, Giorgio S. Effect of hypoxia on macrophage infection by Leishmania amazonensis. J Parasitol. 2004;90:510–5.PubMedCrossRefGoogle Scholar
  57. 57.
    Degrosolli A, Colhone MC, Arrais-Silva WW, Giorgio S. Hypoxia modulates expression of the 70-kD heat shock protein and reduces Leishmania infection in macrophages. J Biomed Sci. 2004;11:847–54.Google Scholar
  58. 58.
    Degrossoli A, Bosetto MC, Lima CB, Giorgio S. Expression of hypoxia-inducible factor 1α in mononuclear phagocytes infected with Leishmania amazonensis. Immunol Lett. 2007;114:119–25.PubMedCrossRefGoogle Scholar
  59. 59.
    Degrossoli A, Arrais-Silva WW, Colhone MC, Gadelha FR, Joazeiro PJ, Giorgio S. The influence of low oxygen on macrophage response to Leishmania infection. Scand J Immunol. 2011;74:165–75.PubMedCrossRefGoogle Scholar
  60. 60.
    Murdoch C, Giannoudis A, Lewis CE. Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues. Blood. 2004;104:2224–34.PubMedCrossRefGoogle Scholar
  61. 61.
    Rahat MA, Bitterman H, Lahat N. Molecular mechanisms regulating macrophage response to hypoxia. Front Immunol. 2011;2:45.PubMedCrossRefGoogle Scholar
  62. 62.
    Bosco MC, Puppo M, Blengio F, Fraone T, Cappello P, Giovarelli M, et al. Monocytes and dendritic cells in a hypoxic environment: spotlights on chemotaxis and migration. Immunobiology. 2008;213:733–49.PubMedCrossRefGoogle Scholar
  63. 63.
    Murdoch C, Muthana M, Lewis CE. Hypoxia regulates macrophage functions in inflammation. J Immunol. 2005;175:6257–63.PubMedGoogle Scholar
  64. 64.
    Lahat N, Rahat MA, Ballan M, Weiss-Cerem L, Engelmayer M, Bitterman H. Hypoxia reduces CD80 expression on monocytes but enhances their LPS-stimulated TNF-alpha secretion. J Leukoc Biol. 2003;74:197–205.PubMedCrossRefGoogle Scholar
  65. 65.
    Spear W, Chan D, Coppens I, Johnson RS, Giaccia A, Blader IJ. The host cell transcription factor hypoxia-inducible factor 1 is required for Toxoplasma gondii growth and survival at physiological oxygen levels. Cell Microbiol. 2006;8:339–52.PubMedCrossRefGoogle Scholar
  66. 66.
    Nickel D, Busch M, Mayer D, Hagemann B, Knoll V, Stenger S. Hypoxia triggers the expression of human β defensin 2 and antimicrobial activity against Mycobacterium tuberculosis in human macrophages. J Immunol. 2012;188:4001–7.PubMedCrossRefGoogle Scholar
  67. 67.
    Puppo M, Bosco MC, Federico M, Pastorino S, Varesio L. Hypoxia inhibits Moloney murine leukemia virus expression in activated macrophages. J Leukoc Biol. 2007;81:528–38.PubMedCrossRefGoogle Scholar
  68. 68.
    Degrossoli A, Giorgio S. Functional alterations in macrophages after hypoxia selection. Exp Biol Med. 2007;232:88–95.Google Scholar
  69. 69.
    Leroux A, Ferrere G, Godie V, Cailleux F, Cailleux F, Renoud ML, Gaudin F, et al. Toxic lipids stored by Kupffer cells correlates with their pro-inflammatory phenotype at an early stage of steatohepatitis. J Hepatol. 2012;57:141–9.PubMedCrossRefGoogle Scholar
  70. 70.
    Lorne E, Zmijewski JW, Zhao X, Liu G, Tsuruta Y, Park Y-J, Dupont H, Abraham E. Role of extracellular superoxide in neutrophil activation: interactions between xanthine oxidase and TLR4 induce proinflammatory cytokine production. Am J Physiol Cell Physiol. 2008;294:C985–93.PubMedCrossRefGoogle Scholar
  71. 71.
    Nicholas SA, Coughlan K, Yasinska I, Lall GS, Gibbs BF, Calzolai L, Sumbayev VV. Dysfunctional mitochondria contain endogenous high-affinity human Toll-like receptor 4 (TLR4) ligands and induce TLR4-mediated inflammatory reactions. Int J Biochem Cell Biol. 2011;43:674–81.PubMedCrossRefGoogle Scholar
  72. 72.
    Romagnoli M, Gomez-Cabrera MC, Perrelli MG, Biasi F, Pallardó FV, Sastre J, Poli G, Viña J. Xanthine oxidase-induced oxidative stress causes activation of NF-kappaB and inflammation in the liver of type I diabetic rats. Free Radic Biol Med. 2010;49:171–7.PubMedCrossRefGoogle Scholar
  73. 73.
    Lewis CL, Pollard JW. Distincts roles of macrophages in different tumor microenvironments. Cancer Res;2006 pp. 605–612.Google Scholar
  74. 74.
    Pettersen JS, Fuentes-Duculan J, Suárez-Fariñas M, Pierson KC, Pitts-Kiefer A, Fan L, et al. Tumor-associated macrophages in the cutaneous SCC microenvironment are heterogeneously activated. J Invest Dermatol. 2011;131:1322–30.PubMedCrossRefGoogle Scholar
  75. 75.
    Stofanko M, Kwon SY, Badenhorst P. Lineage tracing of lamellocytes demonstrates Drosophila macrophage plasticity. PLoS ONE. 2010;5:e14051.PubMedCrossRefGoogle Scholar
  76. 76.
    DeWitt TJ, Scheiner SM. Phenotypic plasticity. Functional and conceptual approaches. New York: Oxford University Press; 2004.Google Scholar
  77. 77.
    Pigliucci M. Phenotypic plasticity: beyond nature and nurture. Baltimore: University Press; 2001.Google Scholar
  78. 78.
    Schlichting CD, Pigliucci M. Phenotypic evolution: a reaction norm perspective. Sunderland: Sinauer; 1998.Google Scholar
  79. 79.
    Chevin LM, Lande R, Mace GM. Adaptation, plasticity, and extinction in a changing environment: towards a predictive theory. PLos Biol;2010 p. e1000357.Google Scholar
  80. 80.
    Svennungsen TO, Holen ØH, Leimar O. Inducible defenses: continuous reaction norms or threshold traits? Am Nat. 2011;178:397–410.PubMedCrossRefGoogle Scholar
  81. 81.
    Fuller T. The integrative biology of phenotypic plasticity. Biol Philos. 2003;18:381–9.CrossRefGoogle Scholar
  82. 82.
    Stearns SC. The evolutionary significance of phenotypic plasticity. Bioscience. 1989;39:436–45.CrossRefGoogle Scholar
  83. 83.
    Dodson S. Predator-induced reaction norms. Bioscience. 1989;39:447–51.CrossRefGoogle Scholar
  84. 84.
    Ebert D. A genome for the environment. Science. 2011;331:539–40.PubMedCrossRefGoogle Scholar
  85. 85.
    Daley JM, Brancato SK, Thomay AA, Reichner JS, Albina JE. The phenotype of murine wound macrophages. J Leukoc Biol. 2010;87:59–67.PubMedCrossRefGoogle Scholar
  86. 86.
    Xu W, Zhao X, Daha MR, et al. Reversible differentiation of pro- and anti-inflammatory macrophages. Mol Immunol. 2013;53:179–86.PubMedCrossRefGoogle Scholar
  87. 87.
    Piersma T, van Gils JA. The flexible phenotype. A body-centred integration of ecology, physiology, and behavior. New York: Oxford University Press; 2011.Google Scholar
  88. 88.
    Whitman DW, Agrawal AA. What is phenotypic plasticity and why is it important? In: Whitman DW, Ananthakrishnan TN, editors. Phenotypic Plasticity of Insects: mechanisms and consequences. Enfield: Science Publishers; 2009. p. 1–63.CrossRefGoogle Scholar
  89. 89.
    Lof ME, Reed TE, McNamara JM, Visser ME. Timing in a fluctuating environment: environmental variability and asymmetric fitness curves can lead to adaptively mismatched avian reproduction. Proc Biol Sci. 2012;279:3161–9.PubMedCrossRefGoogle Scholar
  90. 90.
    Jenkins SJ, Ruckerl D, Cook PC, Jones LH, Finkelman FD, van Rooijen N, et al. Local macrophage proliferation, rather than recruitment from the blood, is a signature of TH2 inflammation. Science. 2011;332:1284–8.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel 2013

Authors and Affiliations

  1. 1.Department of Animal Biology, Biology InstituteUniversidade Estadual de CampinasCampinasBrazil

Personalised recommendations