Review Article | Published:

Macrophage biology in development, homeostasis and disease

Nature volume 496, pages 445455 (25 April 2013) | Download Citation

Abstract

Macrophages, the most plastic cells of the haematopoietic system, are found in all tissues and show great functional diversity. They have roles in development, homeostasis, tissue repair and immunity. Although tissue macrophages are anatomically distinct from one another, and have different transcriptional profiles and functional capabilities, they are all required for the maintenance of homeostasis. However, these reparative and homeostatic functions can be subverted by chronic insults, resulting in a causal association of macrophages with disease states. In this Review, we discuss how macrophages regulate normal physiology and development, and provide several examples of their pathophysiological roles in disease. We define the ‘hallmarks’ of macrophages according to the states that they adopt during the performance of their various roles, taking into account new insights into the diversity of their lineages, identities and regulation. It is essential to understand this diversity because macrophages have emerged as important therapeutic targets in many human diseases.

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References

  1. 1.

    et al. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nature Immunol. 13, 1118–1128 (2012)This paper provides a detailed analysis of the macrophage transcriptome. Several novel genes are identified that are distinctly and universally associated with mature tissue-resident macrophages, but the results also illustrate the extreme diversity of these cell types.

  2. 2.

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

  3. 3.

    & Macrophage plasticity and polarization: in vivo veritas. J. Clin. Invest. 122, 787–795 (2012)

  4. 4.

    et al. Development of monocytes, macrophages, and dendritic cells. Science 327, 656–661 (2010)

  5. 5.

    et al. Local macrophage proliferation, rather than recruitment from the blood, is a signature of TH2 inflammation. Science 332, 1284–1288 (2011)This paper shows that tissue macrophages can proliferate in response to IL-4, suggesting that monocyte recruitment and definitive haematopoiesis may not be required for macrophage expansion in type 2 immunity.

  6. 6.

    et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336, 86–90 (2012)Together with refs 10 and 11, this paper indicates that the mononuclear phagocytic lineage needs to be reassessed and that most resident adult macrophage populations derive from the yolk sac.

  7. 7.

    & Protective and pathogenic functions of macrophage subsets. Nature Rev. Immunol. 11, 723–737 (2011)

  8. 8.

    & Macrophages: master regulators of inflammation and fibrosis. Semin. Liver Dis. 30, 245–257 (2010)A comprehensive review examining the regulatory role of macrophages in chronic inflammatory disease and fibrosis.

  9. 9.

    & Monocyte and macrophage heterogeneity. Nature Rev. Immunol. 5, 953–964 (2005)The definitive review of activated and alternatively activated macrophages, with detailed explanations of the definitions and restrictions of these terms.

  10. 10.

    et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010)

  11. 11.

    et al. Adult Langerhans cells derive predominantly from embryonic fetal liver monocytes with a minor contribution of yolk sac-derived macrophages. J. Exp. Med. 209, 1167–1181 (2012)

  12. 12.

    et al. A defect of CD16-positive monocytes can occur without disease. Immunobiology 218, 169–174 (2013)

  13. 13.

    Macrophages as APC and the dendritic cell myth. J. Immunol. 181, 5829–5835 (2008)

  14. 14.

    , , & Re(de)fining the dendritic cell lineage. Nature Immunol. 13, 1145–1154 (2012)

  15. 15.

    & Colony-stimulating factor-1 in immunity and inflammation. Curr. Opin. Immunol. 18, 39–48 (2006)

  16. 16.

    , , , & Absence of colony stimulation factor-1 receptor results in loss of microglia, disrupted brain development and olfactory deficits. PLoS ONE 6, e26317 (2011)

  17. 17.

    et al. Functional overlap but differential expression of CSF-1 and IL-34 in their CSF-1 receptor-mediated regulation of myeloid cells. J. Leukoc. Biol. 8, 495–505 (2010)

  18. 18.

    et al. IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. Nature Immunol. 13, 753–760 (2012)

  19. 19.

    Trophic macrophages in development and disease. Nature Rev. Immunol. 9, 259–270 (2009)

  20. 20.

    et al. Vascular endothelial growth factor can substitute for macrophage colony-stimulating dactor in the support of osteoclastic bone resorption. J. Exp. Med. 190, 293–298 (1999)

  21. 21.

    & Colony stimulating factors and myeloid cell biology in health and disease. Trends Immunol. 34, 81–89 (2013)

  22. 22.

    et al. Deciphering the transcriptional network of the dendritic cell lineage. Nature Immunol. 13, 888–899 (2012)

  23. 23.

    The complexity of constitutive and inducible gene expression in mononuclear phagocytes. J. Leukoc. Biol. (2012)

  24. 24.

    & Advances in osteoclast biology: old findings and new insights from mouse models. Nature Rev. Rheumatol. 7, 235–243 (2011)

  25. 25.

    et al. The human syndrome of dendritic cell, monocyte, B and NK lymphoid deficiency. J. Exp. Med. 208, 227–234 (2011)

  26. 26.

    , , & Metchnikoff's policemen: macrophages in development, homeostasis and regeneration. Trends Mol. Med. (2011)

  27. 27.

    , , , & Resident macrophages influence stem cell activity in the mammary gland. Breast Cancer Res. 11, R62 (2009)

  28. 28.

    , , , & Activated macrophages are an adaptive element of the colonic epithelial progenitor niche necessary for regenerative responses to injury. Proc. Natl Acad. Sci. USA 102, 99–104 (2005)

  29. 29.

    et al. Bone marrow CD169+ macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche. J. Exp. Med. 208, 261–271 (2011)This paper, together with refs 27, 28 and 30, shows that macrophages regulate various stem cell niches.

  30. 30.

    et al. Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Nature Med. 18, 572–579 (2012)

  31. 31.

    et al. Requirement of DNase II for definitive erythropoiesis in the mouse fetal liver. Science 292, 1546–1549 (2001)

  32. 32.

    et al. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell 138, 271–285 (2009)

  33. 33.

    , , & Regulation of steady-state neutrophil homeostasis by macrophages. Blood 117, 618–629 (2011)

  34. 34.

    et al. Targeted disruption of the mouse CSF-1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased primititive progenitor cell frequencies and reproductive defects. Blood 99, 111–120 (2002)

  35. 35.

    , , & A blast from the past: clearance of apoptotic cells regulates immune responses. Nature Rev. Immunol. 2, 965–975 (2002)

  36. 36.

    et al. Obligatory participation of macrophages in an angiopoietin 2-mediated cell death switch. Development 134, 4449–4458 (2007)

  37. 37.

    et al. Regulation of angiogenesis by a non-canonical Wnt-Flt1 pathway in myeloid cells. Nature 474, 511–515 (2011)An important paper showing the molecular basis of the macrophage regulation of angiogenesis through the WNT pathway.

  38. 38.

    et al. VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling. Nature Cell Biol. 13, 1202–1213 (2011)

  39. 39.

    et al. Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction. Blood 116, 829–840 (2010)

  40. 40.

    et al. Macrophages define dermal lymphatic vessel calibre during development by regulating lymphatic endothelial cell proliferation. Development 137, 3899–3910 (2010)

  41. 41.

    et al. Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism. Nature Med. 15, 545–552 (2009)

  42. 42.

    et al. The CSF-1 receptor ligands IL-34 and CSF-1 exhibit distinct developmental brain expression patterns and regulate neural progenitor cell maintenance and maturation. Dev. Biol. 367, 100–113 (2012)

  43. 43.

    , , , & Reciprocal regulation between resting microglial dynamics and neuronal activity in vivo. Dev. Cell 23, 1189–1202 (2012)A paper that demonstrates that microglia regulate neuronal activity in zebrafish using intravital imaging.

  44. 44.

    et al. Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456–1458 (2011)

  45. 45.

    et al. Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. Nature Genet. 44, 200–205 (2011)

  46. 46.

    et al. Neuroprotection and progenitor cell renewal in the injured adult murine retina requires healing monocyte-derived macrophages. J. Exp Med. 208, 23–39 (2011)

  47. 47.

    et al. Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J. Neurosci. 29, 13435–13444 (2009)

  48. 48.

    , , & Macrophage presence is essential for the regeneration of ascending afferent fibres following a conditioning sciatic nerve lesion in adult rats. BMC Neurosci. 12, 11 (2011)

  49. 49.

    Inflammation and metabolic disorders. Nature 444, 860–867 (2006)

  50. 50.

    , & Macrophage-mediated inflammation in metabolic disease. Nature Rev. Immunol. 11, 738–749 (2011)

  51. 51.

    & Pleiotropic actions of insulin resistance and inflammation in metabolic homeostasis. Science 339, 172–177 (2013)

  52. 52.

    & Macrophages, inflammation, and insulin resistance. Annu. Rev. Physiol. 72, 219–246 (2010)

  53. 53.

    & Adipocytes as regulators of energy balance and glucose homeostasis. Nature 444, 847–853 (2006)

  54. 54.

    , & Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J. Clin. Invest. 117, 175–184 (2007)

  55. 55.

    et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796–1808 (2003)

  56. 56.

    et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest. 112, 1821–1830 (2003)This paper, together with ref. 55, was the first to demonstrate that obesity results in infiltration of WAT by macrophages, which contributes to its inflamed nature.

  57. 57.

    , & Adipose tissue remodeling and obesity. J. Clin. Invest. 121, 2094–2101 (2011)

  58. 58.

    et al. Adipocyte-derived Th2 cytokines and myeloid PPARδ regulate macrophage polarization and insulin sensitivity. Cell Metab. 7, 485–495 (2008)

  59. 59.

    et al. 7, 485–495 Kruppel-like factor 4 regulates macrophage polarization. J. Clin. Invest. 121, 2736–2749 (2011)

  60. 60.

    et al. Macrophage-specific PPARγ controls alternative activation and improves insulin resistance. Nature 447, 1116–1120 (2007)This paper showed that residence of AAMs in WAT is necessary for the maintenance of insulin sensitivity in obese animals.

  61. 61.

    et al. Alternative M2 activation of Kupffer cells by PPARδ ameliorates obesity-induced insulin resistance. Cell Metab. 7, 496–507 (2008)

  62. 62.

    et al. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science. 332, 243–247 (2011)

  63. 63.

    et al. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J. Clin. Invest. 116, 115–124 (2006)

  64. 64.

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

  65. 65.

    & Towards a molecular understanding of adaptive thermogenesis. Nature 404, 652–660 (2000)

  66. 66.

    et al. Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. Nature 480, 104–108 (2011)This paper demonstrated a physiological function for AAMs in sustaining adaptive thermogenesis, which allows mammals to adapt to cold environments.

  67. 67.

    & Mechanisms for insulin resistance: common threads and missing links. Cell 148, 852–871 (2012)

  68. 68.

    et al. Depletion of liver Kupffer cells prevents the development of diet-induced hepatic steatosis and insulin resistance. Diabetes 59, 347–357 (2010)

  69. 69.

    et al. Saturated fatty acid and TLR signaling link beta cell dysfunction and islet inflammation. Cell Metab. 15, 518–533 (2012)

  70. 70.

    et al. Increased number of islet-associated macrophages in type 2 diabetes. Diabetes 56, 2356–2370 (2007)

  71. 71.

    & Nonresolving inflammation. Cell 140, 871–882 (2010)

  72. 72.

    et al. An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice. J. Clin. Invest. 121, 985–997 (2011)

  73. 73.

    et al. IRF5 promotes inflammatory macrophage polarization and TH1–TH17 responses. Nature Immunol. 12, 231–238 (2011)This paper showed that IRF5 expression is induced in macrophages in response to inflammatory stimuli and that this contributes to the polarization of macrophages with an inflammatory phenotype, which causes TH1 and TH17 cells to respond.

  74. 74.

    et al. Inhibition of Mac-1 (CD11b/CD18) enhances tumor response to radiation by reducing myeloid cell recruitment. Proc. Natl Acad. Sci. USA 107, 8363–8368 (2010)

  75. 75.

    & Macrophage diversity enhances tumor progression and metastasis. Cell 141, 39–51 (2010)

  76. 76.

    & Cancer-related inflammation: common themes and therapeutic opportunities. Semin. Cancer Biol. 22, 33–40 (2012)

  77. 77.

    et al. Interferon-gamma links ultraviolet radiation to melanomagenesis in mice. Nature 469, 548–553 (2011)

  78. 78.

    et al. A novel mouse model of inflammatory bowel disease links mammalian target of rapamycin-dependent hyperproliferation of colonic epithelium to inflammation-associated tumorigenesis. Am. J. Pathol. 176, 952–967 (2010)

  79. 79.

    et al. Intestinal inflammation targets cancer-inducing activity of the microbiota. Science 338, 120–123 (2012)

  80. 80.

    , & Interactions between lymphocytes and myeloid cells regulate pro- versus anti-tumor immunity. Cancer Metastasis Rev. 29, 309–316 (2010)

  81. 81.

    & Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21, 309–322 (2012)

  82. 82.

    & Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124, 263–266 (2006)

  83. 83.

    et al. CCL18 from tumor-associated macrophages promotes breast cancer metastasis via PITPNM3. Cancer Cell 19, 541–555 (2011)

  84. 84.

    & Proteolytic networks in cancer. Trends Cell Biol. 21, 228–237 (2011)

  85. 85.

    , & Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141, 52–67 (2010)

  86. 86.

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

  87. 87.

    et al. Targeting the ANG2/TIE2 axis inhibits tumor growth and metastasis by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells. Cancer Cell 19, 512–526 (2011)

  88. 88.

    , , & The role of myeloid cells in the promotion of tumour angiogenesis. Nature Rev. Cancer 8, 618–631 (2008)

  89. 89.

    et al. Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis. Nature 456, 814–818 (2008)

  90. 90.

    et al. Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells. Nature Biotechnol. 25, 911–920 (2007)

  91. 91.

    et al. HIF1α induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 13, 206–220 (2008)

  92. 92.

    et al. Vascular endothelial growth factor restores delayed tumor progression in tumors depleted of macrophages. Mol. Oncol. 1, 288–302 (2007)

  93. 93.

    & The metastatic niche: adapting the foreign soil. Nature Rev. Cancer 9, 285–293 (2009)

  94. 94.

    et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nature Med. 18, 883–891 (2012)

  95. 95.

    et al. Recruitment of monocytes/macrophages by tissue factor-mediated coagulation is essential for metastatic cell survival and premetastatic niche establishment in mice. Blood 119, 3164–3175 (2012)

  96. 96.

    et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475, 222–225 (2011)This paper suggests that macrophages may represent a therapeutic target to prevent tumour cell metastatic seeding and growth.

  97. 97.

    & Leukocytes in mammary development and cancer. Cold Spring Harb. Perspect. Biol. 3, a003285 (2011)

  98. 98.

    & Dynamic education of macrophages in different areas of human tumors. Cancer Microenvironment 5, 195–201 (2012)

  99. 99.

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

  100. 100.

    et al. Role of c-MYC in alternative activation of human macrophages and tumor-associated macrophage biology. Blood 119, 411–421 (2012)

  101. 101.

    et al. An ets2-driven transcriptional program in tumor-associated macrophages promotes tumor metastasis. Cancer Res. 70, 1323–1333 (2010)

  102. 102.

    & The immune system in atherosclerosis. Nature Immunol. 12, 204–212 (2011)

  103. 103.

    et al. Unique CD14 intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-γ axis. J. Clin. Invest. 118, 2269–2280 (2008)

  104. 104.

    , & Progress and challenges in translating the biology of atherosclerosis. Nature 473, 317–325 (2011)

  105. 105.

    et al. A restricted subset of dendritic cells captures airborne antigens and remains able to activate specific T cells long after antigen exposure. Immunity 16, 271–283 (2002)

  106. 106.

    et al. Adoptive transfer of IL-4Rα+ macrophages is sufficient to enhance eosinophilic inflammation in a mouse model of allergic lung inflammation. BMC Immunol. 13, 6 (2012)

  107. 107.

    et al. Serum amyloid P attenuates M2 macrophage activation and protects against fungal spore-induced allergic airway disease. J. Allergy Clin. Immunol. 126, 712–721 (2010)

  108. 108.

    et al. More alternative activation of macrophages in lungs of asthmatic patients. J. Allergy Clin. Immunol. 127, 831–833 (2011)

  109. 109.

    et al. Allergic airway disease is unaffected by the absence of IL-4Rα-dependent alternatively activated macrophages. J. Allergy Clin. Immunol. 130, 743–750 (2012)

  110. 110.

    & Obstacles and opportunities for understanding macrophage polarization. J. Leukoc. Biol. 89, 557–563 (2011)

  111. 111.

    , , , & MicroRNA-124 promotes microglia quiescence and suppresses EAE by deactivating macrophages via the C/EBP-α-PU.1 pathway. Nature Med. 17, 64–70 (2011)

  112. 112.

    , , , & An independent subset of TLR expressing CCR2-dependent macrophages promotes colonic inflammation. J. Immunol. 184, 6843–6854 (2010)

  113. 113.

    , , , & Inflammation switches the differentiation program of Ly6Chi monocytes from antiinflammatory macrophages to inflammatory dendritic cells in the colon. J. Exp. Med. 209, 139–155 (2012)

  114. 114.

    et al. Macrophages suppress T cell responses and arthritis development in mice by producing reactive oxygen species. J. Clin. Invest. 117, 3020–3028 (2007)

  115. 115.

    et al. Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn's disease. J. Exp. Med. 206, 1883–1897 (2009)

  116. 116.

    et al. Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis. Nature Immunol. 10, 1178–1184 (2009)

  117. 117.

    et al. Down-regulation of the macrophage lineage through interaction with OX2 (CD200). Science 290, 1768–1771 (2000)

  118. 118.

    et al. Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice. PLoS Med. 6, e1000113 (2009)

  119. 119.

    et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J. Clin. Invest. 115, 56–65 (2005)

  120. 120.

    & Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nature Med. 18, 1028–1040 (2012)

  121. 121.

    & Exploring the full spectrum of macrophage activation. Nature Rev. Immunol. 8, 958–969 (2008)

  122. 122.

    et al. Macrophage therapy for murine liver fibrosis recruits host effector cells improving fibrosis, regeneration, and function. Hepatology 53, 2003–2015 (2011)

  123. 123.

    et al. An atlas of combinatorial transcriptional regulation in mouse and man. Cell. 140, 744–752 (2010)

  124. 124.

    et al. Transcript profiling of CD16-positive monocytes reveals a unique molecular fingerprint. Eur. J. Immunol. 42, 957–974 (2012)

  125. 125.

    et al. Setup and use of a two-laser multiphoton microscope for multichannel intravital fluorescence imaging. Nature Protocols 6, 1500–1520 (2011)

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Acknowledgements

The authors apologize to colleagues whose papers they were unable to cite on this occasion. T.A.W. is supported by the intramural research program of the National Institutes of Allergy and Infectious Diseases (National Institutes of Health (NIH)). This work was supported by the National Cancer Institute of the NIH (award numbers R01CA131270S, U54HD058155 and PO1CA100324 (to J.W.P.), and HL076746, DK094641 and DK094641 (to A.C.)); the Diabetes Family Fund (to the University of California, San Francisco), an American Heart Association (AHA) Innovative Award (12PILT11840038) and a NIH Director’s Pioneer Award (DP1AR064158 to A.C.).

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Affiliations

  1. Immunopathogenesis Section, Program in Tissue Immunity and Repair and Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20877-8003, USA

    • Thomas A. Wynn
  2. Cardiovascular Research Institute, Department of Physiology and Medicine, University of California San Francisco, California 94158-9001, USA

    • Ajay Chawla
  3. Medical Research Council Centre for Reproductive Health, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK

    • Jeffrey W. Pollard
  4. Center for the Study of Reproductive Biology and Women's Health, Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, New York 10461, USA

    • Jeffrey W. Pollard

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Author Contributions T.A.W., A.C. and J.W.P. contributed to the writing and editing of all aspects of this Review.

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The authors declare no competing financial interests.

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Correspondence to Thomas A. Wynn or Ajay Chawla or Jeffrey W. Pollard.

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https://doi.org/10.1038/nature12034

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