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Tissue biology perspective on macrophages


Macrophages are essential components of mammalian tissues. Although historically known mainly for their function in host defense and the clearance of apoptotic cells, macrophages are now increasingly recognized as serving many roles in tissue development, homeostasis and repair. In addition, tissue-resident macrophages have many tissue-specific functional characteristics, which are a reflection of distinct gene-expression programs. Here we discuss the emerging views of macrophage biology from evolutionary, developmental and homeostatic perspectives.

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Figure 1: The concept of primary and accessory cell types.
Figure 2: Two types of signals that define the functional states of a cell.
Figure 3: Macrophage phenotype is a product of differentiation and polarization.
Figure 4: Transcriptional modules that control macrophage phenotypes.
Figure 5: The macrophage as a homeostatic controller.


  1. 1

    Tauber, A.I. Metchnikoff and the phagocytosis theory. Nat. Rev. Mol. Cell Biol. 4, 897–901 (2003).

    CAS  PubMed  Google Scholar 

  2. 2

    Wynn, T.A., Chawla, A. & Pollard, J.W. Macrophage biology in development, homeostasis and disease. Nature 496, 445–455 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    Gordon, S., Pluddemann, A. & Martinez Estrada, F. Macrophage heterogeneity in tissues: phenotypic diversity and functions. Immunol. Rev. 262, 36–55 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Pollard, J.W. Trophic macrophages in development and disease. Nat. Rev. Immunol. 9, 259–270 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Mantovani, A. et al. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 25, 677–686 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Moore, K.J. & Tabas, I. Macrophages in the pathogenesis of atherosclerosis. Cell 145, 341–355 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Boyle, W.J., Simonet, W.S. & Lacey, D.L. Osteoclast differentiation and activation. Nature 423, 337–342 (2003).

    CAS  PubMed  Google Scholar 

  8. 8

    Chawla, A., Nguyen, K.D. & Goh, Y.P. Macrophage-mediated inflammation in metabolic disease. Nat. Rev. Immunol. 11, 738–749 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Olefsky, J.M. & Glass, C.K. Macrophages, inflammation, and insulin resistance. Annu. Rev. Physiol. 72, 219–246 (2010).

    CAS  PubMed  Google Scholar 

  10. 10

    Wynn, T.A. & Barron, L. Macrophages: master regulators of inflammation and fibrosis. Semin. Liver Dis. 30, 245–257 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Noy, R. & Pollard, J.W. Tumor-associated macrophages: from mechanisms to therapy. Immunity 41, 49–61 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Gordon, S. et al. Localization and function of tissue macrophages. Ciba Found. Symp. 118, 54–67 (1986).

    CAS  PubMed  Google Scholar 

  13. 13

    Epelman, S., Lavine, K.J. & Randolph, G.J. Origin and functions of tissue macrophages. Immunity 41, 21–35 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Ginhoux, F. & Jung, S. Monocytes and macrophages: developmental pathways and tissue homeostasis. Nat. Rev. Immunol. 14, 392–404 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Varol, C., Mildner, A. & Jung, S. Macrophages: development and tissue specialization. Annu. Rev. Immunol. 33, 643–675 (2015).

    CAS  PubMed  Google Scholar 

  16. 16

    Sieweke, M.H. & Allen, J.E. Beyond stem cells: self-renewal of differentiated macrophages. Science 342, 1242974 (2013).

    PubMed  Google Scholar 

  17. 17

    Gautier, E.L. et al. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat. Immunol. 13, 1118–1128 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Gosselin, D. et al. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell 159, 1327–1340 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Lavin, Y. et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159, 1312–1326 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

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

    CAS  Google Scholar 

  21. 21

    Davies, L.C., Jenkins, S.J., Allen, J.E. & Taylor, P.R. Tissue-resident macrophages. Nat. Immunol. 14, 986–995 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Hussell, T. & Bell, T.J. Alveolar macrophages: plasticity in a tissue-specific context. Nat. Rev. Immunol. 14, 81–93 (2014).

    CAS  Google Scholar 

  23. 23

    Parkhurst, C.N. et al. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155, 1596–1609 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Kohyama, M. et al. Role for Spi-C in the development of red pulp macrophages and splenic iron homeostasis. Nature 457, 318–321 (2009).

    CAS  Google Scholar 

  25. 25

    Dranoff, G. et al. Involvement of granulocyte-macrophage colony-stimulating factor in pulmonary homeostasis. Science 264, 713–716 (1994).

    CAS  PubMed  Google Scholar 

  26. 26

    Suzuki, T. et al. Pulmonary macrophage transplantation therapy. Nature 514, 450–454 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Arendt, D. The evolution of cell types in animals: emerging principles from molecular studies. Nat. Rev. Genet. 9, 868–882 (2008).

    CAS  PubMed  Google Scholar 

  28. 28

    Hickman, C.P., Roberts, L.S. & Larson, A. in Integrated Principles of Zoology (McGraw-Hill Science, 2009).

    Google Scholar 

  29. 29

    Egeblad, M., Nakasone, E.S. & Werb, Z. Tumors as organs: complex tissues that interface with the entire organism. Dev. Cell 18, 884–901 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

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

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Hanahan, D. & Weinberg, R.A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Knecht, A.K. & Bronner-Fraser, M. Induction of the neural crest: a multigene process. Nat. Rev. Genet. 3, 453–461 (2002).

    CAS  PubMed  Google Scholar 

  33. 33

    Butovsky, O. et al. Identification of a unique TGF-β-dependent molecular and functional signature in microglia. Nat. Neurosci. 17, 131–143 (2014).

    CAS  PubMed  Google Scholar 

  34. 34

    Okabe, Y. & Medzhitov, R. Tissue-specific signals control reversible program of localization and functional polarization of macrophages. Cell 157, 832–844 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Gerhart, J. & Kirschner, M. The theory of facilitated variation. Proc. Natl. Acad. Sci. USA 104 Suppl 1, 8582–8589 (2007).

    CAS  PubMed  Google Scholar 

  36. 36

    Haldar, M. et al. Heme-mediated SPI-C induction promotes monocyte differentiation into iron-recycling macrophages. Cell 156, 1223–1234 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Schneider, C. et al. Induction of the nuclear receptor PPAR-γ by the cytokine GM-CSF is critical for the differentiation of fetal monocytes into alveolar macrophages. Nat. Immunol. 15, 1026–1037 (2014).

    CAS  Google Scholar 

  38. 38

    Hanayama, R. et al. Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice. Science 304, 1147–1150 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Gorgani, N.N., Ma, Y. & Clark, H.F. Gene signatures reflect the marked heterogeneity of tissue-resident macrophages. Immunol. Cell Biol. 86, 246–254 (2008).

    CAS  PubMed  Google Scholar 

  40. 40

    Lawrence, T. & Natoli, G. Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat. Rev. Immunol. 11, 750–761 (2011).

    CAS  PubMed  Google Scholar 

  41. 41

    Glass, C.K. Genetic and genomic approaches to understanding macrophage identity and function. Arterioscler. Thromb. Vasc. Biol. 35, 755–762 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Mossadegh-Keller, N. et al. M-CSF instructs myeloid lineage fate in single haematopoietic stem cells. Nature 497, 239–243 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Sauka-Spengler, T. & Bronner-Fraser, M. A gene regulatory network orchestrates neural crest formation. Nat. Rev. Mol. Cell Biol. 9, 557–568 (2008).

    CAS  PubMed  Google Scholar 

  44. 44

    Rosas, M. et al. The transcription factor Gata6 links tissue macrophage phenotype and proliferative renewal. Science 344, 645–648 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Gautier, E.L. et al. Gata6 regulates aspartoacylase expression in resident peritoneal macrophages and controls their survival. J. Exp. Med. 211, 1525–1531 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Stout, R.D. & Suttles, J. Functional plasticity of macrophages: reversible adaptation to changing microenvironments. J. Leukoc. Biol. 76, 509–513 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    A-Gonzalez, N. et al. The nuclear receptor LXRa controls the functional specialization of splenic macrophages. Nat. Immunol. 14, 831–839 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Tacke, R. et al. The transcription factor NR4A1 is essential for the development of a novel macrophage subset in the thymus. Sci. Rep. 5, 10055 (2015).

    PubMed  PubMed Central  Google Scholar 

  49. 49

    Cannon, W.B. Organization for physiological homeostasis. Physiol. Rev. 9, 399–431 (1929).

    Google Scholar 

  50. 50

    Kotas, M.E. & Medzhitov, R. Homeostasis, inflammation, and disease susceptibility. Cell 160, 816–827 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Chovatiya, R. & Medzhitov, R. Stress, inflammation, and defense of homeostasis. Mol. Cell 54, 281–288 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Lewis, C.E. & Pollard, J.W. Distinct role of macrophages in different tumor microenvironments. Cancer Res. 66, 605–612 (2006).

    CAS  PubMed  Google Scholar 

  53. 53

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

    CAS  PubMed  Google Scholar 

  54. 54

    Takeuchi, O. & Akira, S. Pattern recognition receptors and inflammation. Cell 140, 805–820 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Geijtenbeek, T.B. & Gringhuis, S.I. Signalling through C-type lectin receptors: shaping immune responses. Nat. Rev. Immunol. 9, 465–479 (2009).

    CAS  PubMed  Google Scholar 

  56. 56

    Lamkanfi, M. & Dixit, V.M. Mechanisms and functions of inflammasomes. Cell 157, 1013–1022 (2014).

    CAS  Google Scholar 

  57. 57

    Rathinam, V.A., Vanaja, S.K. & Fitzgerald, K.A. Regulation of inflammasome signaling. Nat. Immunol. 13, 333–342 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Sun, L., Wu, J., Du, F., Chen, X. & Chen, Z.J. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 339, 786–791 (2013).

    CAS  Google Scholar 

  59. 59

    Nagata, S., Hanayama, R. & Kawane, K. Autoimmunity and the clearance of dead cells. Cell 140, 619–630 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Lemke, G. & Rothlin, C.V. Immunobiology of the TAM receptors. Nat. Rev. Immunol. 8, 327–336 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Desai, B.N. & Leitinger, N. Purinergic and calcium signaling in macrophage function and plasticity. Front. Immunol. 5, 580 (2014).

    PubMed  PubMed Central  Google Scholar 

  62. 62

    Lattin, J. et al. G-protein-coupled receptor expression, function, and signaling in macrophages. J. Leukoc. Biol. 82, 16–32 (2007).

    CAS  PubMed  Google Scholar 

  63. 63

    Link, T.M. et al. TRPV2 has a pivotal role in macrophage particle binding and phagocytosis. Nat. Immunol. 11, 232–239 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Kashio, M. et al. Redox signal-mediated sensitization of transient receptor potential melastatin 2 (TRPM2) to temperature affects macrophage functions. Proc. Natl. Acad. Sci. USA 109, 6745–6750 (2012).

    CAS  PubMed  Google Scholar 

  65. 65

    Compan, V. et al. Cell volume regulation modulates NLRP3 inflammasome activation. Immunity 37, 487–500 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Ip, W.K. & Medzhitov, R. Macrophages monitor tissue osmolarity and induce inflammatory response through NLRP3 and NLRC4 inflammasome activation. Nat. Commun. 6, 6931 (2015).

    CAS  PubMed  Google Scholar 

  67. 67

    Liu, P.T. et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311, 1770–1773 (2006).

    CAS  PubMed  Google Scholar 

  68. 68

    Ganeshan, K. & Chawla, A. Metabolic regulation of immune responses. Annu. Rev. Immunol. 32, 609–634 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Hansson, G.K. & Hermansson, A. The immune system in atherosclerosis. Nat. Immunol. 12, 204–212 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Moore, K.J., Sheedy, F.J. & Fisher, E.A. Macrophages in atherosclerosis: a dynamic balance. Nat. Rev. Immunol. 13, 709–721 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Oh, D.Y. et al. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 142, 687–698 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Rahman, M. et al. The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages. Nat. Commun. 5, 3944 (2014).

    CAS  PubMed  Google Scholar 

  73. 73

    Weigert, A., Weis, N. & Brune, B. Regulation of macrophage function by sphingosine-1-phosphate. Immunobiology 214, 748–760 (2009).

    CAS  PubMed  Google Scholar 

  74. 74

    McCutcheon, J.C. et al. Regulation of macrophage phagocytosis of apoptotic neutrophils by adhesion to fibronectin. J. Leukoc. Biol. 64, 600–607 (1998).

    CAS  PubMed  Google Scholar 

  75. 75

    Santiago-García, J., Kodama, T. & Pitas, R.E. The class A scavenger receptor binds to proteoglycans and mediates adhesion of macrophages to the extracellular matrix. J. Biol. Chem. 278, 6942–6946 (2003).

    PubMed  Google Scholar 

  76. 76

    Franco, C. et al. Discoidin domain receptor 1 on bone marrow-derived cells promotes macrophage accumulation during atherogenesis. Circ. Res. 105, 1141–1148 (2009).

    CAS  PubMed  Google Scholar 

  77. 77

    Leitinger, B. Transmembrane collagen receptors. Annu. Rev. Cell Dev. Biol. 27, 265–290 (2011).

    CAS  PubMed  Google Scholar 

  78. 78

    Sturge, J., Todd, S.K., Kogianni, G., McCarthy, A. & Isacke, C.M. Mannose receptor regulation of macrophage cell migration. J. Leukoc. Biol. 82, 585–593 (2007).

    CAS  PubMed  Google Scholar 

  79. 79

    Woo, H.J., Shaw, L.M., Messier, J.M. & Mercurio, A.M. The major non-integrin laminin binding protein of macrophages is identical to carbohydrate binding protein 35 (Mac-2). J. Biol. Chem. 265, 7097–7099 (1990).

    CAS  PubMed  Google Scholar 

  80. 80

    McKee, C.M. et al. Hyaluronan (HA) fragments induce chemokine gene expression in alveolar macrophages. The role of HA size and CD44. J. Clin. Invest. 98, 2403–2413 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Jang, J.Y. et al. Conditional ablation of LYVE-1+ cells unveils defensive roles of lymphatic vessels in intestine and lymph nodes. Blood 122, 2151–2161 (2013).

    CAS  PubMed  Google Scholar 

  82. 82

    Termeer, C. et al. Oligosaccharides of Hyaluronan activate dendritic cells via toll-like receptor 4. J. Exp. Med. 195, 99–111 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

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We thank members of the Medzhitov laboratory for discussions, and L. Kopp for reading the manuscript. Supported by The Blavatnik Family Foundation, Else Kröner-Fresenius-Stiftung, the US National Institutes of Health (AI046688, AI089771 and CA157461) and the Howard Hughes Medical Institute (all for research in the Medzhitov laboratory).

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Correspondence to Ruslan Medzhitov.

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Okabe, Y., Medzhitov, R. Tissue biology perspective on macrophages. Nat Immunol 17, 9–17 (2016).

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