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Monocyte and macrophage heterogeneity

Key Points

  • Peripheral-blood monocytes show morphological, antigenic and functional heterogeneity.

  • Bone-marrow monocytes that are released into the circulation express distinct receptors for chemokines and adhesion molecules and are preferentially recruited to inflammatory lesions, where they can differentiate into macrophages or dendritic cells (DCs). These monocytes have high phagocytic activity, are known as 'inflammatory' monocytes and are identified by a CC-chemokine receptor 2 (CCR2)+ CX3C-chemokine receptor 1 (CX3CR1)lowLy6C+ phenotype in mice and a CD14hiCD16CD64+CCR2+CX3CR1low phenotype in humans.

  • Cells that constitute the other main subset of monocytes, which seems to be derived from the inflammatory monocytes in peripheral blood, seem to enter tissues under steady-state conditions, where they can contribute to the replenishment of tissue-resident populations of macrophages and DCs. These cells have been called 'resident' monocytes, and one of the functional differences between these monocytes and inflammatory monocytes is that resident monocytes have greater accessory activity in mixed leukocyte reactions. They are identified by a CCR2CX3CR1hiLy6C phenotype in mice and a CD14+CD16+CD64CX3CR1hi phenotype in humans.

  • An intermediate phenotype of monocyte has also been observed, and these cells might be developmental intermediates. Similar to inflammatory monocytes, they respond to pro-inflammatory cues, but they also have high stimulatory activity in T-cell-stimulation assays, similar to resident monocytes. They have been suggested to be a monocyte subset that is recruited to inflammatory lesions and is prone to differentiate into DCs. They are identified by an intermediate phenotype in mice (CCR2+CX3CR1midLy6Cmid) and might be present in humans as CD14+CD16+CD64+ monocytes.

  • Tissue-resident macrophage populations are replenished by a combination of local proliferation of precursors and recruitment of bone-marrow-derived precursors. In most cases, it has not been formally shown whether monocytes or specific lineage-committed precursors fulfil this role.

  • The mechanism of replenishment of tissue-resident populations is greatly influenced by the presence of inflammation or injury, because under these conditions, a greater dependence on circulating precursors is evident in model systems.

Abstract

Heterogeneity of the macrophage lineage has long been recognized and, in part, is a result of the specialization of tissue macrophages in particular microenvironments. Circulating monocytes give rise to mature macrophages and are also heterogeneous themselves, although the physiological relevance of this is not completely understood. However, as we discuss here, recent studies have shown that monocyte heterogeneity is conserved in humans and mice, allowing dissection of its functional relevance: the different monocyte subsets seem to reflect developmental stages with distinct physiological roles, such as recruitment to inflammatory lesions or entry to normal tissues. These advances in our understanding have implications for the development of therapeutic strategies that are targeted to modify particular subpopulations of monocytes.

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Figure 1: Development and function of monocyte subsets in mice.
Figure 2: Origins of mature cells in the periphery in adult mice.
Figure 3: Macrophage heterogeneity during inflammation.

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References

  1. Volkman, A. & Gowans, J. L. The origin of macrophages from human bone marrow in the rat. Br. J. Exp. Pathol. 46, 62–70 (1965).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. van Furth, R. & Cohn, Z. A. The origin and kinetics of mononuclear phagocytes. J. Exp. Med. 128, 415–435 (1968).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Ebert, R. H. & Florey, H. W. The extravascular development of the monocyte observed in vivo. Brit. J. Exp. Pathol. 20, 342–356 (1939).

    Google Scholar 

  4. van Furth, R., Diesselhoff-den Dulk, M. M. & Mattie, H. Quantitative study on the production and kinetics of mononuclear phagocytes during an acute inflammatory reaction. J. Exp. Med. 138, 1314–1330 (1973).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Imhof, B. A. & Aurrand-Lions, M. Adhesion mechanisms regulating the migration of monocytes. Nature Rev. Immunol. 4, 432–444 (2004).

    Article  CAS  Google Scholar 

  6. 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). Characterization of antigenically distinct monocyte subsets in human peripheral blood.

    Article  CAS  PubMed  Google Scholar 

  7. Ziegler-Heitbrock, H. W. et al. The novel subset of CD14+/CD16+ blood monocytes exhibits features of tissue macrophages. Eur. J. Immunol. 23, 2053–2058 (1993).

    Article  CAS  PubMed  Google Scholar 

  8. Weber, C. et al. Differential chemokine receptor expression and function in human monocyte subpopulations. J. Leukoc. Biol. 67, 699–704 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. Sallusto, F. & Lanzavecchia, A. Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor α. J. Exp. Med. 179, 1109–1118 (1994).

    Article  CAS  PubMed  Google Scholar 

  10. Sanchez-Torres, C., Garcia-Romo, G. S., Cornejo-Cortes, M. A., Rivas-Carvalho, A. & Sanchez-Schmitz, G. CD16+ and CD16 human blood monocyte subsets differentiate in vitro to dendritic cells with different abilities to stimulate CD4+ T cells. Int. Immunol. 13, 1571–1581 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Randolph, G. J., Beaulieu, S., Lebecque, S., Steinman, R. M. & Muller, W. A. Differentiation of monocytes into dendritic cells in a model of transendothelial trafficking. Science 282, 480–483 (1998).

    Article  CAS  PubMed  Google Scholar 

  12. Randolph, G. J., Sanchez-Schmitz, G., Liebman, R. M. & Schakel, K. The CD16+ (FcγRIII+) subset of human monocytes preferentially becomes migratory dendritic cells in a model tissue setting. J. Exp. Med. 196, 517–527 (2002). Identification that the CD16+ human peripheral-blood monocyte subset preferentially differentiates into DCs after endothelial reverse transmigration.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ancuta, P. et al. Fractalkine preferentially mediates arrest and migration of CD16+ monocytes. J. Exp. Med. 197, 1701–1707 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Grage-Griebenow, E. et al. Identification of a novel dendritic cell-like subset of CD64+/CD16+ blood monocytes. Eur. J. Immunol. 31, 48–56 (2001).

    Article  CAS  PubMed  Google Scholar 

  15. Grage-Griebenow, E., Flad, H. D. & Ernst, M. Heterogeneity of human peripheral blood monocyte subsets. J. Leukoc. Biol. 69, 11–20 (2001).

    CAS  PubMed  Google Scholar 

  16. Palframan, R. T. et al. Inflammatory chemokine transport and presentation in HEV: a remote control mechanism for monocyte recruitment to lymph nodes in inflamed tissues. J. Exp. Med. 194, 1361–1373 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kuziel, W. A. et al. Severe reduction in leukocyte adhesion and monocyte extravasation in mice deficient in CC chemokine receptor 2. Proc. Natl Acad. Sci. USA 94, 12053–12058 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kurihara, T., Warr, G., Loy, J. & Bravo, R. Defects in macrophage recruitment and host defense in mice lacking the CCR2 chemokine receptor. J. Exp. Med. 186, 1757–1762 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lu, B. et al. Abnormalities in monocyte recruitment and cytokine expression in monocyte chemoattractant protein 1-deficient mice. J. Exp. Med. 187, 601–608 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gu, L. et al. Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Mol. Cell 2, 275–281 (1998).

    Article  CAS  PubMed  Google Scholar 

  21. Serbina, N. V., Salazar-Mather, T. P., Biron, C. A., Kuziel, W. A. & Pamer, E. G. TNF/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection. Immunity 19, 59–70 (2003).

    Article  CAS  PubMed  Google Scholar 

  22. Geissmann, F., Jung, S. & Littman, D. R. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19, 71–82 (2003). The first modern functional characterization and cell-fate studies of mouse peripheral-blood monocyte subsets during steady-state conditions and inflammation.

    Article  CAS  PubMed  Google Scholar 

  23. Tedder, T. F., Steeber, D. A. & Pizcueta, P. L-selectin-deficient mice have impaired leukocyte recruitment into inflammatory sites. J. Exp. Med. 181, 2259–2264 (1995).

    Article  CAS  PubMed  Google Scholar 

  24. Rosen, S. D. Ligands for L-selectin: homing, inflammation, and beyond. Annu. Rev. Immunol. 22, 129–156 (2004).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  26. de Bruijn, M. F. et al. Distinct mouse bone marrow macrophage precursors identified by differential expression of ER-MP12 and ER-MP20 antigens. Eur. J. Immunol. 24, 2279–2284 (1994).

    Article  CAS  PubMed  Google Scholar 

  27. 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).

    Article  CAS  PubMed  Google Scholar 

  28. Qu, C. et al. Role of CCR8 and other chemokine pathways in the migration of monocyte-derived dendritic cells to lymph nodes. J. Exp. Med. 200, 1231–1241 (2004). Suggestion that a third, intermediate monocyte phenotype in mouse peripheral blood might be an inflammatory monocyte that is prone to differentiate into DCs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ahuja, V., Miller, S. E. & Howell, D. N. Identification of two subpopulations of rat monocytes expressing disparate molecular forms and quantities of CD43. Cell. Immunol. 163, 59–69 (1995).

    Article  CAS  PubMed  Google Scholar 

  30. Chamorro, S. et al. Phenotypic characterization of monocyte subpopulations in the pig. Immunobiology 202, 82–93 (2000).

    Article  CAS  PubMed  Google Scholar 

  31. Chamorro, S. et al. Phenotypic and functional heterogeneity of porcine blood monocytes and its relation with maturation. Immunology 114, 63–71 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Chamorro, S. et al. In vitro differentiation of porcine blood CD163 and CD163+ monocytes into functional dendritic cells. Immunobiology 209, 57–65 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Gordon, S. Biology of the macrophage. J. Cell Sci. Suppl. 4, 267–286 (1986).

    Article  CAS  PubMed  Google Scholar 

  34. Gordon, S. The role of the macrophage in immune regulation. Res. Immunol. 149, 685–688 (1998).

    Article  CAS  PubMed  Google Scholar 

  35. Austyn, J. M. & Gordon, S. F4/80, a monoclonal antibody directed specifically against the mouse macrophage. Eur. J. Immunol. 11, 805–815 (1981).

    Article  CAS  PubMed  Google Scholar 

  36. Dijkstra, C. D., Van Vliet, E., Dopp, E. A., van der Lelij, A. A. & Kraal, G. Marginal zone macrophages identified by a monoclonal antibody: characterization of immuno- and enzyme-histochemical properties and functional capacities. Immunology 55, 23–30 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Kraal, G. & Janse, M. Marginal metallophilic cells of the mouse spleen identified by a monoclonal antibody. Immunology 58, 665–669 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Quinn, J. M. & Gillespie, M. T. Modulation of osteoclast formation. Biochem. Biophys. Res. Commun. 328, 739–745 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. McCusker, K. & Hoidal, J. Characterization of scavenger receptor activity in resident human lung macrophages. Exp. Lung Res. 15, 651–661 (1989).

    Article  CAS  PubMed  Google Scholar 

  40. Palecanda, A. et al. Role of the scavenger receptor MARCO in alveolar macrophage binding of unopsonized environmental particles. J. Exp. Med. 189, 1497–1506 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Taylor, P. R. et al. The β-glucan receptor, dectin-1, is predominantly expressed on the surface of cells of the monocyte/macrophage and neutrophil lineages. J. Immunol. 169, 3876–3882 (2002).

    Article  CAS  PubMed  Google Scholar 

  42. Surh, C. D. & Sprent, J. T-cell apoptosis detected in situ during positive and negative selection in the thymus. Nature 372, 100–103 (1994).

    Article  CAS  PubMed  Google Scholar 

  43. Tabe, H., Kawabata, I., Koba, R. & Homma, T. Cell dynamics in the germinal center of the human tonsil. Acta Otolaryngol. Suppl. 523, 64–67 (1996).

    CAS  Google Scholar 

  44. Smythies, L. E. et al. Human intestinal macrophages display profound inflammatory anergy despite avid phagocytic and bacteriocidal activity. J. Clin. Invest. 115, 66–75 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. van Furth, R., Diesselhoff-den Dulk, M. M., Sluiter, W. & Van Dissel, J. T. in Mononuclear Phagocytes: Characteristics, Physiology and Function (ed. van Furth, R.) 201–210 (Martinus Nijhoff, Dordrecht, 1985).

    Book  Google Scholar 

  46. Merad, M. et al. Langerhans cells renew in the skin throughout life under steady-state conditions. Nature Immunol. 3, 1135–1141 (2002). Interesting demonstration of the differences in requirement for circulating precursors or local proliferation in the renewal of Langerhans cells during steady-state conditions and inflammation.

    Article  CAS  Google Scholar 

  47. Kanitakis, J., Petruzzo, P. & Dubernard, J. M. Turnover of epidermal Langerhans' cells. N. Engl. J. Med. 351, 2661–2662 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Kurihara, N., Chenu, C., Miller, M., Civin, C. & Roodman, G. D. Identification of committed mononuclear precursors for osteoclast-like cells formed in long term human marrow cultures. Endocrinology 126, 2733–2741 (1990).

    Article  CAS  PubMed  Google Scholar 

  49. Udagawa, N. et al. Origin of osteoclasts: mature monocytes and macrophages are capable of differentiating into osteoclasts under a suitable microenvironment prepared by bone marrow-derived stromal cells. Proc. Natl Acad. Sci. USA 87, 7260–7264 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Matsuzaki, K. et al. Osteoclast differentiation factor (ODF) induces osteoclast-like cell formation in human peripheral blood mononuclear cell cultures. Biochem. Biophys. Res. Commun. 246, 199–204 (1998).

    Article  CAS  PubMed  Google Scholar 

  51. Marks, S. C. Jr & Lane, P. W. Osteopetrosis, a new recessive skeletal mutation on chromosome 12 of the mouse. J. Hered. 67, 11–18 (1976).

    Article  PubMed  Google Scholar 

  52. Yoshida, H. et al. The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature 345, 442–444 (1990).

    Article  CAS  PubMed  Google Scholar 

  53. Kong, Y. Y. et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397, 315–323 (1999).

    Article  CAS  PubMed  Google Scholar 

  54. Arai, F. et al. Commitment and differentiation of osteoclast precursor cells by the sequential expression of c-Fms and receptor activator of nuclear factor κB (RANK) receptors. J. Exp. Med. 190, 1741–1754 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Sawyer, R. T., Strausbauch, P. H. & Volkman, A. Resident macrophage proliferation in mice depleted of blood monocytes by strontium-89. Lab. Invest. 46, 165–170 (1982).

    CAS  PubMed  Google Scholar 

  56. Tarling, J. D., Lin, H. S. & Hsu, S. Self-renewal of pulmonary alveolar macrophages: evidence from radiation chimera studies. J. Leukoc. Biol. 42, 443–446 (1987).

    Article  CAS  PubMed  Google Scholar 

  57. Matute-Bello, G. et al. Optimal timing to repopulation of resident alveolar macrophages with donor cells following total body irradiation and bone marrow transplantation in mice. J. Immunol. Methods 292, 25–34 (2004).

    Article  CAS  PubMed  Google Scholar 

  58. Thomas, E. D., Ramberg, R. E., Sale, G. E., Sparkes, R. S. & Golde, D. W. Direct evidence for a bone marrow origin of the alveolar macrophage in man. Science 192, 1016–1018 (1976).

    Article  CAS  PubMed  Google Scholar 

  59. Nakata, K. et al. Augmented proliferation of human alveolar macrophages after allogeneic bone marrow transplantation. Blood 93, 667–673 (1999).

    Article  CAS  PubMed  Google Scholar 

  60. Stanley, E. et al. Granulocyte/macrophage colony-stimulating factor-deficient mice show no major perturbation of hematopoiesis but develop a characteristic pulmonary pathology. Proc. Natl Acad. Sci. USA 91, 5592–5596 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Hamilton, J. A. GM-CSF in inflammation and autoimmunity. Trends Immunol. 23, 403–408 (2002).

    Article  CAS  PubMed  Google Scholar 

  62. Hickey, W. F. Leukocyte traffic in the central nervous system: the participants and their roles. Semin. Immunol. 11, 125–137 (1999).

    Article  CAS  PubMed  Google Scholar 

  63. Lawson, L. J., Perry, V. H. & Gordon, S. Turnover of resident microglia in the normal adult mouse brain. Neuroscience 48, 405–415 (1992).

    Article  CAS  PubMed  Google Scholar 

  64. de Groot, C. J., Huppes, W., Sminia, T., Kraal, G. & Dijkstra, C. D. Determination of the origin and nature of brain macrophages and microglial cells in mouse central nervous system, using non-radioactive in situ hybridization and immunoperoxidase techniques. Glia 6, 301–309 (1992).

    Article  CAS  PubMed  Google Scholar 

  65. Kraal, G. Cells in the marginal zone of the spleen. Int. Rev. Cytol. 132, 31–74 (1992).

    Article  CAS  PubMed  Google Scholar 

  66. Taylor, P. R. et al. Macrophage receptors and immune recognition. Annu. Rev. Immunol. 23, 901–944 (2005).

    Article  CAS  PubMed  Google Scholar 

  67. van der Laan, L. J. et al. Regulation and functional involvement of macrophage scavenger receptor MARCO in clearance of bacteria in vivo. J. Immunol. 162, 939–947 (1999).

    CAS  PubMed  Google Scholar 

  68. Kang, Y. S. et al. SIGN-R1, a novel C-type lectin expressed by marginal zone macrophages in spleen, mediates uptake of the polysaccharide dextran. Int. Immunol. 15, 177–186 (2003).

    Article  CAS  PubMed  Google Scholar 

  69. Geijtenbeek, T. B. et al. Marginal zone macrophages express a murine homologue of DC-SIGN that captures blood-borne antigens in vivo. Blood 100, 2908–2916 (2002).

    Article  CAS  PubMed  Google Scholar 

  70. Taylor, P. R. et al. Development of a specific system for targeting protein to metallophilic macrophages. Proc. Natl Acad. Sci. USA 101, 1963–1968 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Eloranta, M. L. & Alm, G. V. Splenic marginal metallophilic macrophages and marginal zone macrophages are the major interferon-α/β producers in mice upon intravenous challenge with herpes simplex virus. Scand. J. Immunol. 49, 391–394 (1999).

    Article  CAS  PubMed  Google Scholar 

  72. van Furth, R. & Diesselhoff-den Dulk, M. M. Dual origin of mouse spleen macrophages. J. Exp. Med. 160, 1273–1283 (1984).

    Article  CAS  PubMed  Google Scholar 

  73. van Rooijen, N., Kors, N. & Kraal, G. Macrophage subset repopulation in the spleen: differential kinetics after liposome-mediated elimination. J. Leukoc. Biol. 45, 97–104 (1989).

    Article  CAS  PubMed  Google Scholar 

  74. Van Rooijen, N., Kors, N., van de Ende, M. & Dijkstra, C. D. Depletion and repopulation of macrophages in spleen and liver of rat after intravenous treatment with liposome-encapsulated dichloromethylene diphosphonate. Cell Tissue Res. 260, 215–222 (1990).

    Article  CAS  PubMed  Google Scholar 

  75. Wijffels, J. F., de Rover, Z., Beelen, R. H., Kraal, G. & van Rooijen, N. Macrophage subpopulations in the mouse spleen renewed by local proliferation. Immunobiology 191, 52–64 (1994).

    Article  CAS  PubMed  Google Scholar 

  76. Witmer-Pack, M. D. et al. Identification of macrophages and dendritic cells in the osteopetrotic (op/op) mouse. J. Cell Sci. 104, 1021–1029 (1993).

    Article  PubMed  Google Scholar 

  77. Takahashi, K., Umeda, S., Shultz, L. D., Hayashi, S. & Nishikawa, S. Effects of macrophage colony-stimulating factor (M-CSF) on the development, differentiation, and maturation of marginal metallophilic macrophages and marginal zone macrophages in the spleen of osteopetrosis (op) mutant mice lacking functional M-CSF activity. J. Leukoc. Biol. 55, 581–588 (1994).

    Article  CAS  PubMed  Google Scholar 

  78. Cecchini, M. G. et al. Role of colony stimulating factor-1 in the establishment and regulation of tissue macrophages during postnatal development of the mouse. Development 120, 1357–1372 (1994).

    Article  CAS  PubMed  Google Scholar 

  79. Crofton, R. W., Diesselhoff-den Dulk, M. M. & van Furth, R. The origin, kinetics, and characteristics of the Kupffer cells in the normal steady state. J. Exp. Med. 148, 1–17 (1978).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Naito, M., Hasegawa, G. & Takahashi, K. Development, differentiation, and maturation of Kupffer cells. Microsc. Res. Tech. 39, 350–364 (1997).

    Article  CAS  PubMed  Google Scholar 

  81. Bouwens, L., Baekeland, M., De Zanger, R. & Wisse, E. Quantitation, tissue distribution and proliferation kinetics of Kupffer cells in normal rat liver. Hepatology 6, 718–722 (1986).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  85. Takeda, K., Kaisho, T. & Akira, S. Toll-like receptors. Annu. Rev. Immunol. 21, 335–376 (2003).

    Article  CAS  PubMed  Google Scholar 

  86. Davies, J. R., Rudd, J. F., Fryer, T. D. & Weissberg, P. L. Targeting the vulnerable plaque: the evolving role of nuclear imaging. J. Nucl. Cardiol. 12, 234–246 (2005).

    Article  PubMed  Google Scholar 

  87. Aschoff, L. Das Reticulo-endotheliale System. Ergeb. Inn. Med. Kinderheilkd. 26, 1–118 (1924) (in German).

    Google Scholar 

  88. Lichanska, A. M. & Hume, D. A. Origins and functions of phagocytes in the embryo. Exp. Hematol. 28, 601–611 (2000).

    Article  CAS  PubMed  Google Scholar 

  89. Shepard, J. L. & Zon, L. I. Developmental derivation of embryonic and adult macrophages. Curr. Opin. Hematol. 7, 3–8 (2000).

    Article  CAS  PubMed  Google Scholar 

  90. Takahashi, K., Donovan, M. J., Rogers, R. A. & Ezekowitz, R. A. Distribution of murine mannose receptor expression from early embryogenesis through to adulthood. Cell Tissue Res. 292, 311–323 (1998).

    Article  CAS  PubMed  Google Scholar 

  91. Hughes, D. A. & Gordon, S. Expression and function of the type 3 complement receptor in tissues of the developing mouse. J. Immunol. 160, 4543–4552 (1998).

    CAS  PubMed  Google Scholar 

  92. Hume, D. A., Monkley, S. J. & Wainwright, B. J. Detection of c-fms protooncogene in early mouse embryos by whole mount in situ hybridization indicates roles for macrophages in tissue remodelling. Br. J. Haematol. 90, 939–942 (1995).

    Article  CAS  PubMed  Google Scholar 

  93. Herbomel, P., Thisse, B. & Thisse, C. Ontogeny and behaviour of early macrophages in the zebrafish embryo. Development 126, 3735–3745 (1999).

    Article  CAS  PubMed  Google Scholar 

  94. Henderson, R. B., Hobbs, J. A., Mathies, M. & Hogg, N. Rapid recruitment of inflammatory monocytes is independent of neutrophil migration. Blood 102, 328–335 (2003).

    Article  CAS  PubMed  Google Scholar 

  95. Taylor, P. R., Brown, G. D., Geldhof, A. B., Martinez-Pomares, L. & Gordon, S. Pattern recognition receptors and differentiation antigens define murine myeloid cell heterogeneity ex vivo. Eur. J. Immunol. 33, 2090–2097 (2003).

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Siamon Gordon.

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DATABASES

Entrez Gene

CCR2

CD14

CD16

CD43

CD62L

CD163

CX3CR1

Ly6C

Glossary

OSTEOCLAST

A multinucleate cell that resorbs bone.

AFFERENT LYMPHATIC VESSEL

A vessel that carries lymph into a lymph node.

MIXED LEUKOCYTE REACTION

A tissue-culture technique for testing T-cell reactivity. The proliferation of one population of T cells, induced by exposure to inactivated MHC-mismatched stimulator cells, is determined by measuring the incorporation of 3H-thymidine into the DNA of dividing cells.

CLODRONATE-LOADED LIPOSOME

A liposome that contains the drug dichloromethylene diphosphonate. These liposomes are ingested by macrophages, resulting in cell death.

DIL-LABELLED LIPOSOSOME

A liposome that is labelled with the fluorochrome Dil (1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate). These liposomes are internalized by phagocytic cells, rendering the cells fluorescent.

PERITONEUM

The membrane that lines the abdominal cavity.

STERILE PERITONITIS

Inflammation of the peritoneum that is induced by sterile injection of an irritant, such as thioglycollate broth. This results in the sequential recruitment of granulocytes, monocytes and lymphocytes. It is widely used to study acute inflammation.

EFFERENT LYMPHATIC VESSEL

A vessel that carries lymph out of a lymph node.

PATTERN-RECOGNITION RECEPTOR

A type of receptor that binds conserved molecular structures that are found in pathogens. Examples include the mannose receptor, which binds terminally mannosylated and polymannosylated compounds, and Toll-like receptors, which are activated by various microbial products, such as bacterial lipopolysaccharides, hypomethylated DNA, flagellin and double-stranded RNA.

SCAVENGER RECEPTOR

A cell-surface receptor that is involved in the internalization of selected polyanionic ligands, including modified low-density lipoproteins.

TINGIBLE-BODY MACROPHAGE

A type of macrophage that is present in the splenic white pulp and is involved in the clearance of apoptotic cells.

LAMINA PROPRIA

The connective tissue that underlies the epithelium of the gut mucosa. It contains various myeloid and lymphoid cells, including macrophages, dendritic cells, T cells and B cells.

LANGERHANS CELL

A professional antigen-presenting dendritic cell that is localized in the epidermal layer of the skin.

BONE-MARROW CHIMERA

An individual that has received a transplant of bone marrow from another individual.

PARABIOTIC MICE

Mice that share a circulatory system as a result of surgical connection.

GRANULOCYTE/MACROPHAGE COLONY-FORMING-UNIT PRECURSOR

(GM-CFU precursor). A committed precursor in haematopoietic tissues that can form granulocytes and macrophages in the presence of specific growth factors.

OSTEOPETROTIC MICE

(Mcsfop/Mcsfop mice). An inbred strain of mice that suffers from osteopetrosis (stony bones) as a result of deficient function of osteoclasts. The defect has been localized to the gene that encodes macrophage colony-stimulating factor (M-CSF; also known as CSF1).

ALVEOLAR PROTEINOSIS

A disease that is caused by accumulation of surfactant proteins in the alveoli.

MICROGLIAL CELL

A type of macrophage that is derived from bone marrow, arborized and present in the parenchyma of the central nervous system.

PERIVASCULAR MACROPHAGE

A type of macrophage that lines small blood vessels: for example, near the surface of the brain.

MENINGEAL MACROPHAGE

A type of macrophages that is present in the meninges (the three membranes that surround the brain).

CHOROID-PLEXUS MACROPHAGE

A type of macrophage that is present at the interface between the blood and the cerebrospinal fluid in the brain.

MARGINAL-ZONE MACROPHAGE

A type of macrophage that is present in the splenic marginal zone and is involved in the recognition and clearance of material, such as pathogen-derived material, from the splenic circulation.

METALLOPHILIC MACROPHAGE

A type of macrophage that surrounds the splenic white pulp, adjacent to the marginal sinus.

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Gordon, S., Taylor, P. Monocyte and macrophage heterogeneity. Nat Rev Immunol 5, 953–964 (2005). https://doi.org/10.1038/nri1733

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