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  • Review Article
  • Published:

Alternative activation of macrophages

Key Points

  • Macrophages are a heterogeneous population of resident and recruited cells that are found in all organs and are involved in tissue homeostasis and defence of the host.

  • The cells express a wide range of surface receptors, which mediate their recognition of endogenous and microbial ligands.

  • Activation of macrophages by surface ligands and cytokines induces a spectrum of pro- and anti-inflammatory states, which are responsible for immune activation and deactivation.

  • The T helper 2 (TH2) cytokines interleukin-4 (IL-4) and IL-13 induce a characteristic, stereotypical, 'alternative' activation state of macrophages that is distinct from the 'classical' TH1-type activation by interferon-γ and deactivation by IL-10 and transforming growth factor-β.

  • The effects of IL-4 and IL-13 on macrophages contribute to clearance, presentation of antigens and repair in allergic immune reactions and parasite-induced granuloma formation.

  • Useful markers of alternative macrophage activation include induction of expression of the mannose receptor, MHC class II molecules and selected chemokines, as well as new gene products that have been discovered by gene-expression studies.

  • In this review, I argue for a more limited definition of alternative activation by IL-4 and IL-13, which act through a common receptor subunit, and I distinguish this form of activation from other forms of immunomodulation.

  • This model lends itself to further study of macrophages by gene profiling and proteomics, and it might become extended to a range of other forms of modified immune responses, with potential therapeutic benefits.

Abstract

The classical pathway of interferon-γ-dependent activation of macrophages by T helper 1 (TH1)-type responses is a well-established feature of cellular immunity to infection with intracellular pathogens, such as Mycobacterium tuberculosis and HIV. The concept of an alternative pathway of macrophage activation by the TH2-type cytokines interleukin-4 (IL-4) and IL-13 has gained credence in the past decade, to account for a distinctive macrophage phenotype that is consistent with a different role in humoral immunity and repair. In this review, I assess the evidence in favour of alternative macrophage activation in the light of macrophage heterogeneity, and define its limits and relevance to a range of immune and inflammatory conditions.

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Figure 1: Innate and acquired immune activation of macrophages.
Figure 2: Differential utilization of L-arginine by activated macrophages.

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References

  1. Mackaness, G. B. The immunological basis of acquired cellular resistance. J. Exp. Med. 120, 105 (1964). An early delineation of macrophage activation by intracellular infection.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Gordon, S. in Fundamental Immunology 4th edn Ch. 15 (ed. Paul, W.) 533–545 (Lippincott Raven, Philadelphia, 1999).

    Google Scholar 

  3. Gordon, S. in Immunology 6th edn (eds Roitt, I., Brostoff, B. & Male, D.) 147–162 (Mosby, Edinburgh, 2001).

    Google Scholar 

  4. Hamilton, T. in The Macrophage 2nd edn (eds Burke, B. & Lewis, C. E.) 73–102 (Oxford Univ. Press, 2002).

    Google Scholar 

  5. Dalton, D. K. et al. Multiple defects of immune-cell function in mice with disrupted interferon-γ genes. Science 259, 1739–1742 (1993). The definitive proof that IFN-γ is a 'classical activator' of macrophage anti-microbial activity and is an inducer of the expression of MHC class II molecules and NOS2.

    Article  CAS  PubMed  Google Scholar 

  6. Ehrt, S. et al. Reprogramming of the macrophage transcriptome in response to interferon-γ and Mycobacterium tuberculosis. Signaling roles of nitric oxide synthase-2 and phagocyte oxidase. J. Exp. Med. 194, 1123–1140 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Boldrick, J. C. et al. Stereotyped and specific gene-expression programs in human innate immune responses to bacteria. Proc. Natl Acad. Sci. USA 99, 972–977 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Nau, G. J. et al. Human macrophage activation programs induced by bacterial pathogens. Proc. Natl Acad. Sci. USA 99, 1503–1508 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 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 

  10. Mills, C. D., Kincaid, K., Alt, J. M., Heilman, M. J. & Hill, A. M. M-1/M-2 macrophages and the TH1/TH2 paradigm. J. Immunol. 164, 6166–6173 (2000).

    Article  CAS  PubMed  Google Scholar 

  11. Tzachanis, D., Berezovskaya, A., Nadler, L. M. & Boussiotis, V. A. Blockade of B7/CD28 in mixed lymphocyte reaction cultures results in the generation of alternatively activated macrophages, which suppress T-cell responses. Blood 99, 1465–1473 (2002).

    Article  CAS  PubMed  Google Scholar 

  12. Peiser, L., Mukhopadhyay, S. & Gordon, S. Scavenger receptors in innate immunity. Curr. Opin. Immunol. 14, 123–128 (2002).

    Article  CAS  PubMed  Google Scholar 

  13. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ravetch, J. V. & Bolland, S. IgG Fc receptors. Annu. Rev. Immunol. 19, 275–290 (2001).

    Article  CAS  PubMed  Google Scholar 

  15. Barrington, R., Zhang, M., Fischer, M. & Carroll, M. C. The role of complement in inflammation and adaptive immunity. Immunol. Rev. 180, 5–15 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Crouch, E. C. & Whitsett, J. A. in Innate Immunity (eds Ezekowitz, R. A. B. & Hoffman, J. A.) 205–229 (Humana, Totowa, New Jersey, 2002).

    Book  Google Scholar 

  17. Tobias, P. A. in Innate Immunity (eds Ezekowitz, R. A. B. & Hoffman, J. A.) 255–265 (Humana, Totowa, New Jersey, 2002).

    Book  Google Scholar 

  18. Kaisho, T. & Akira, S. in Innate Immunity (eds Ezekowitz, R. A. B. & Hoffman, J. A.) 177–189 (Humana, Totowa, New Jersey, 2002).

    Book  Google Scholar 

  19. Linehan, S. A., Martinez-Pomares, L. & Gordon, S. Macrophage lectins in host defence. Microbes Infect. 2, 279–288 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. de Fougerolles, A. R. et al. Global expression analysis of extracellular matrix–integrin interactions in monocytes. Immunity 13, 749–758 (2000).

    Article  CAS  PubMed  Google Scholar 

  21. Eggleton, P., Tenner, A. J. & Reid, K. M. M. C1q receptors. Clin. Exp. Immunol. 120, 406–412 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Brown, E. J. & Frazier, W. A. Integrin-associated protein (CD47) and its ligands. Trends Cell Biol. 11, 130–135 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. Barclay, A. N., Wright, G. J., Brooke, G. & Brown, M. H. CD200 and membrane protein interactions in the control of myeloid cells. Trends Immunol. 213, 285–290 (2002).

    Article  Google Scholar 

  24. Anderson, C. F. & Mosser, D. M. A novel phenotype for an activated macrophage: the type 2 activated macrophage. J. Leukocyte Biol. 72, 101–106 (2002).

    CAS  PubMed  Google Scholar 

  25. Anderson, C. F. & Mosser, D. M. Cutting edge: biasing immune receptors by directing antigen to macrophage Fcγ receptors. J. Immunol. 168, 3697–3701 (2002).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  27. Bach, E. A., Aguet, M. & Schreiber, R. D. The IFNγ receptor: a paradigm for cytokine receptor signalling. Annu. Rev. Immunol. 15, 563–591 (1997).

    Article  CAS  PubMed  Google Scholar 

  28. Nelms, K., Keegan, A. D., Zamorano, J., Ryan, J. J. & Paul, W. E. The IL-4 receptor: signalling mechanisms and biologic functions. Annu. Rev. Immunol. 17, 701–738 (1999).

    Article  CAS  PubMed  Google Scholar 

  29. Moore, K. W., de Waal Malefyt, R., Coffman, R. L. & O'Garra, A. Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol. 19, 683–765 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Tsunawaki, S., Sporn, M., Ding, A. & Nathan, C. Deactivation of macrophages by transforming growth factor-β. Nature 334, 260 (1988).

    Article  CAS  PubMed  Google Scholar 

  31. O'Garra, A. & Arai, N. The molecular basis of T helper 1 and T helper 2 cell differentiation. Trends Cell Biol. 10, 542–550 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Colonna, M. Can we apply the TH1–TH2 paradigm to all lymphocytes? Nature Immunol. 2, 899–900 (2001).

    Article  CAS  Google Scholar 

  33. Monney, L. et al. TH1-specific cell-surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 415, 536–541 (2002).

    Article  CAS  PubMed  Google Scholar 

  34. Chizzolini, C., Rezzonico, R., De Luca, C., Burger, D. & Dayer, J. -M. TH2 cell membrane factors in association with IL-4 enhance matrix metalloproteinase-1 (MMP-1) while decreasing MMP-9 production by granulocyte–macrophage colony-stimulating factor-differentiated human monocytes. J. Immunol. 164, 5952–5960 (2000).

    Article  CAS  PubMed  Google Scholar 

  35. Banchereau, J. et al. Immunobiology of dendritic cells. Annu. Rev. Immunol. 18, 767–811 (2000).

    Article  CAS  PubMed  Google Scholar 

  36. Shortman, K. & Liu, Y. -J. Mouse and human dendritic-cell subtypes. Nature Immunol. 2, 151–161 (2002). An up-to-date assessment of dendritic-cell heterogeneity.

    Article  CAS  Google Scholar 

  37. Takeda, K., Kamanaka, M., Tanaka, T., Kishimoto, T. & Akira, S. Impaired IL-13-mediated functions of macrophages in STAT6-deficient mice. J. Immunol. 157, 3220–3222 (1996).

    CAS  PubMed  Google Scholar 

  38. Shimoda, K. et al. Lack of IL-4 induced TH2 response and IgE class switching in mice with disrupted Stat6 gene. Nature 380, 630–633 (1996).

    Article  CAS  PubMed  Google Scholar 

  39. McKenzie, G. J. et al. Impaired development of TH2 cells in IL-13-deficient mice. Immunity 9, 423–432 (1998).

    Article  CAS  PubMed  Google Scholar 

  40. Kopf, M., Le, G. G., Coyle, A. J., Kosco, V. M. & Brombacher, F. Immune responses of IL-4, IL-5, IL-6 deficient mice. Immunol. Rev. 148, 45–69 (1995).

    Article  CAS  PubMed  Google Scholar 

  41. McKenzie, G. J., Fallon, P., Emson, C. L., Grencis, R. & McKenzie, A. N. J. Simultaneous disruption of interleukin (IL)-4 and IL-13 defines individual roles in T helper cell type-2-mediated responses. J. Exp. Med. 189, 1565–1572 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Mohrs, M. et al. Differences between IL-4- and IL-4 receptor-α-deficient mice in chronic Leishmaniasis reveal a protective role for IL-13 receptor signalling. J. Immunol. 162, 7302–7308 (1999).

    CAS  PubMed  Google Scholar 

  43. Stein, M., Keshav, S., Harris, N. & Gordon, S. IL-4 potently enhances murine macrophage mannose receptor activity; a marker of alternative immunologic macrophage activation. J. Exp. Med. 176, 287–292 (1992). The first report of the upregulation of expression of macrophage mannose receptor by IL-4, and suggested use of the term 'alternative activation' to distinguish this mechanism from the previously reported downregulation of expression by IFN-γ.

    Article  CAS  PubMed  Google Scholar 

  44. McInnes, A. & Rennick, D. M. Interleukin-4 induces cultured monocytes/macrophages to form giant multinucleated cells. J. Exp. Med. 167, 598–611 (1988).

    Article  CAS  PubMed  Google Scholar 

  45. Mokoena, T. & Gordon, S. Activation of human macrophages. Modulation of mannosyl, fucosyl receptors for endocytosis by lymphokine, γ and α interferons and dexamethasone. J. Clin. Invest. 75, 624–631 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Doyle, A. G. et al. Interleukin-13 alters the activation state of murine macrophages in vitro: comparison with interleukin-4 and interferon-γ. Eur. J. Immunol. 24, 1441–1445 (1994).

    Article  CAS  PubMed  Google Scholar 

  47. Doherty, T. M., Kastelein, R., Menon, S., Andrade, S. & Coffman, R. L. Modulation of murine macrophage function by IL-13. J. Immunol. 151, 7151–7160 (1993).

    CAS  PubMed  Google Scholar 

  48. de Waal Malefyt, R. et al. Effects of IL-13 on phenotype, cytokine production and cytotoxic function of human monocytes. Comparison with IL-4 and modulation by IFN-γ or IL-10. J. Immunol. 151, 6370–6381 (1993).

    CAS  PubMed  Google Scholar 

  49. Hart, P. H. et al. Differential responses of human monocytes and macrophages to IL-4 and IL-13. J. Leukoc. Biol. 66, 575–578 (1999).

    Article  CAS  PubMed  Google Scholar 

  50. Montaner, L. J. et al. Type-1 and type-2 cytokine regulation of macrophage endocytosis: differential activation by IL-4/IL-13 as opposed to IFN-γ or IL-10. J. Immunol. 162, 4606–4613 (1999).

    CAS  PubMed  Google Scholar 

  51. Prigozy, T. I. et al. The mannose receptor delivers lipoglycan antigens to endosomes for presentation to T cells by CD1b molecules. Immunity 6, 187–197 (1997).

    Article  CAS  PubMed  Google Scholar 

  52. Sallusto, F., Cella, M., Danieli, C. & Lanzavecchia, A. Dendritic cells use macropinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class II compartment: downregulation by cytokines and bacterial products. J. Exp. Med. 182, 389–400 (1995).

    Article  CAS  PubMed  Google Scholar 

  53. Martinez-Pomares, L. & Gordon, S. The mannose receptor and its role in antigen presentation. The Immunologist 7, 119–123 (1999).

    CAS  Google Scholar 

  54. Loke, P. et al. IL-4-dependent alternatively activated macrophages have a distinctive in vivo gene-expression phenotype. BMC Immunol. 3, 7 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Takemoto, N. et al. Cutting edge: chromatin remodelling at the IL-4/IL-13 intergenic regulatory region for TH2-specific cytokine gene cluster. J. Immunol. 165, 6687–6691 (2000).

    Article  CAS  PubMed  Google Scholar 

  56. Avni, O. et al. TH-cell differentiation is accompanied by dynamic changes in histone acetylation of cytokine genes. Nature Immunol. 3, 643–651 (2002).

    Article  CAS  Google Scholar 

  57. Saccani, S., Pantano, S. & Natoli, G. Two waves of nuclear factor-κB recruitment to target promoters. J. Exp. Med. 193, 1351–1360 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Sallusto, F. & Lanzavecchia, A. Understanding dendritic-cell and T-lymphocyte traffic through the analysis of chemokine-receptor expression. Immunol. Rev. 177, 134–140 (2000).

    Article  CAS  PubMed  Google Scholar 

  59. Mantovani, A., Locati, M., Vecchi, A., Sozzani, S. & Allavena, P. Decoy receptors: a strategy to regulate inflammatory cytokines and chemokines. Trends Immunol. 22, 328–336 (2001).

    Article  CAS  PubMed  Google Scholar 

  60. Fenton, M. J., Buras, J. A. & Donnelly, R. P. IL-4 reciprocally regulated IL-1 and IL-1 receptor antagonist expression in human monocytes. J. Immunol. 149, 1283–1288 (1992).

    CAS  PubMed  Google Scholar 

  61. Bonecchi, R. et al. Divergent effects of interleukin-4 and interferon-γ on macrophage-derived chemokine production: an amplification circuit of polarized T helper 2 responses. Blood 92, 2668–2671 (1998). A description of a useful chemokine marker (macrophage-derived chemokine) that is consistent with the model of IL-4 versus IFN-γ regulation of macrophage activity, relating to T H 2-polarized responses, by a group that has made several important contributions to this field.

    Article  CAS  PubMed  Google Scholar 

  62. Andrew, D. P. et al. STCP-1 (MDC) CC-chemokine acts specifically on chronically activated TH2 lymphocytes and is produced by monocytes on stimulation with TH2 cytokines IL-4 and IL-13. J. Immunol. 161, 5027–5038 (1998).

    CAS  PubMed  Google Scholar 

  63. Imai, T. et al. Selective recruitment of CCR4-bearing TH2 cells toward antigen-presenting cells by the CC-chemokines thymus and activation-regulated chemokine and macrophage-derived chemokine. Int. Immunol. 11, 81–88 (1999).

    Article  CAS  PubMed  Google Scholar 

  64. Bonecchi, R. et al. Induction of functional IL-8 receptors by IL-4 and IL-13 in human monocytes. J. Immunol. 164, 3862–3869 (2000).

    Article  CAS  PubMed  Google Scholar 

  65. Gordon, S. & Hughes, D. A. in Lung Macrophages and Dendritic Cells in Health & Disease (eds Lipscomb, M. & Russell, S.) 3–31 (Marcel Dekker, New York, 1997).

    Google Scholar 

  66. Zhu, Z. et al. IL-13-induced chemokine responses in the lung: role of CCR2 in the pathogenesis of IL-13-induced inflammation and remodelling. J. Immunol. 168, 2953–2962 (2002).

    Article  CAS  PubMed  Google Scholar 

  67. Traynor, T. R., Kuziel, W. A., Toews, G. B. & Huffnagle, G. B. CCR2 expression determines T1 versus T2 polarization during pulmonary Cryptococcus neoformans infection. J. Immunol. 164, 2021–2027 (2000).

    Article  CAS  PubMed  Google Scholar 

  68. Gu, L., Tseng, S., Horner, R. M., Tam, C., Loda, M. & Rollins, B. J. Control of TH2 polarization by the chemokine monocyte chemoattractant protein-1. Nature 404, 407–411 (2000).

    Article  CAS  PubMed  Google Scholar 

  69. Gao, J. -L. et al. Impaired host defense, hematopoiesis, granulomatous inflammation and type-1–type 2 cytokine balance in mice lacking CC-chemokine receptor 1. J. Exp. Med. 185, 1959–1968 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Medoff, B. D. et al. IFN-γ-inducible protein 10 (CXCL10) contributes to airway hyperreactivity and airway inflammation in a mouse model of asthma. J. Immunol. 168, 5278–5286 (2002).

    Article  CAS  PubMed  Google Scholar 

  71. Fort, M. M. et al. IL-25 induces IL-4, IL-5 and IL-13 and TH2-associated pathologies in vivo. Immunity 15, 985–995 (2001). A description of a new cytokine (IL-25) that induces the production of T H 2 cytokines and associated pathologies in the host.

    Article  CAS  PubMed  Google Scholar 

  72. Ruth, J. H. et al. Interleukin-4 and -13 participation in mycobacterial (type-1) and schistosomal (type-2) antigen-elicited pulmonary granuloma formation: multiparameter analysis of cellular recruitment, chemokine expression and cytokine networks. Cytokine 12, 432–444 (2000). This article explores the role of chemokine receptors in a schistosome granuloma model by groups who have made important contributions to the study of T H 2 immune-cell recruitment and pathology.

    Article  CAS  PubMed  Google Scholar 

  73. Chensue, S. W., Warmington, K., Ruth, J. H., Lukacs, N. & Kunkel, S. L. Mycobacterial and schistosomal antigen-elicited granuloma formation in IFN-γ and IL-4 knockout mice: analysis of local and regional cytokine and chemokine networks. J. Immunol. 159, 3565–3573 (1997).

    CAS  PubMed  Google Scholar 

  74. Warmington, K. S. et al. Effect of CC-chemokine receptor 2 (CCR2) knockout on type-2 (schistosomal antigen-elicited) pulmonary granuloma formation: analysis of cellular recruitment and cytokine responses. Am. J. Pathol. 154, 1407–1416 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Jankovic, D. et al. Schistosome-infected IL-4 receptor knockout (KO) mice, in contrast to IL-4 KO mice, fail to develop granulomatous pathology while maintaining the same lymphokine expression profile. J. Immunol. 163, 337–342 (1999).

    CAS  PubMed  Google Scholar 

  76. Rutschman, R. et al. Cutting edge: Stat6-dependent substrate depletion regulates nitric oxide production. J. Immunol. 166, 2173–2177 (2001).

    Article  CAS  PubMed  Google Scholar 

  77. Munder, M., Eichmann, K. & Modolell, M. Alternative metabolic states in murine macrophages reflected by the nitric oxide synthase/arginase balance: competitive regulation by CD4+ T cells correlates with TH1/TH2 phenotype. J. Immunol. 160, 5347–5354 (1998).

    CAS  PubMed  Google Scholar 

  78. Munder, M. et al. TH1/TH2-regulated expression of arginase isoforms in murine macrophages and dendritic cells. J. Immunol. 163, 3771–3777 (1999).

    CAS  PubMed  Google Scholar 

  79. Hesse, M., Cheever, A. W., Jankovic, D. & Wynn, T. A. NOS-2 mediates the protective anti-inflammatory and antifibrotic effects of the TH1-inducing adjuvant, IL-12, in a TH2 model of granulomatous disease. Am. J. Pathol. 157, 945–955 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. 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 paper describes the link between arginine metabolism and T H 2-cell activation, granuloma formation and repair.

    Article  CAS  PubMed  Google Scholar 

  81. Namangala, B., De Baetselier, P., Noel, W., Brys, L. & Beschin, A. Alternative versus classical macrophage activation during experimental African trypanosomosis. J. Leukocyte Biol. 69, 387–396 (2001).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  83. Welch, J. S. et al. TH2 cytokines and allergic challenge induce Ym1 expression in macrophages by a STAT6-dependent mechanism. J. Biol. Chem. 277, 42821–42829 (2002).

    Article  CAS  PubMed  Google Scholar 

  84. Webb, D. C., McKenzie, A. N. & Foster, P. S. Expression of the Ym2 lectin-binding protein is dependent on interleukin (IL-4) and IL-13 signal transduction: identification of a novel allergy-associated protein. J. Biol. Chem. 276, 41969–41976 (2001).

    Article  CAS  PubMed  Google Scholar 

  85. Loke, P., MacDonald, A. S., Robb, A., Maizels, R. M. & Allen, J. E. Alternatively activated macrophages induced by nematode infection inhibit proliferation via cell-to-cell contact. Eur. J. Immunol. 30, 2669–2678 (2000).

    Article  CAS  PubMed  Google Scholar 

  86. Wegmann, T. G., Lin, H., Guilbert, L. & Mosmann, T. R. Bidirectional cytokine interactions in the maternal–fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol. Today 14, 353–356 (1993).

    Article  CAS  PubMed  Google Scholar 

  87. Dealtry, G. B., O'Farrell, M. K. & Fernandez, N. The TH2 cytokine environment of the placenta. Int. Arch. Allergy Immunol. 123, 107–119 (2000).

    Article  CAS  PubMed  Google Scholar 

  88. Mues, B., Langer, D., Zwadlo, G. & Sorg, C. Phenotypic characterization of macrophages in human term placenta. Immunology 67, 303–307 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Mellor, A. L. et al. Prevention of T-cell-driven complement activation and inflammation by tryptophan catabolism during pregnancy. Nature Immunol. 2, 64–68 (2001).

    Article  CAS  Google Scholar 

  90. Bonney, E. A. & Matzinger, P. Much IDO about pregnancy. Nature Med. 4, 1128–1129 (1998).

    Article  CAS  PubMed  Google Scholar 

  91. Kodelja, V. et al. Differences in angiogenic potential of classically vs alternatively activated macrophages. Immunobiology 197, 478–493 (1997).

    Article  CAS  PubMed  Google Scholar 

  92. Albina, J. E., Mills, C. D., Henry, W. L. Jr & Caldwell, M. D. Temporal expression of different pathways of L-arginine metabolism in healing wounds. J. Immunol. 144, 3877 (1990).

    CAS  PubMed  Google Scholar 

  93. Andersson, P. -B., Perry, V. H. & Gordon, S. The acute inflammatory response to lipopolysaccharide in CNS parenchyma differs from that in other body tissues. Neuroscience 48, 169–186 (1992).

    Article  CAS  PubMed  Google Scholar 

  94. Glass, C. K. & Witztum, J. L. Atherosclerosis, the road ahead. Cell 104, 503–516 (2001). An overview of atherosclerosis as a modified form of inflammatory response, in which macrophages have an important role.

    Article  CAS  PubMed  Google Scholar 

  95. Gupta, S. et al. IFN-γ potentiated atherosclerosis in ApoE knock-out mice. J. Clin. Invest. 99, 2752–2761 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Greaves, D. R. et al. Linked chromosome 16q13 chemokines, macrophage-derived chemokine, fractalkine, and thymus- and activation-regulated chemokine, are expressed in human atherosclerotic lesions. Arterioscler. Thromb. Vasc. Biol. 21, 923–929 (2001).

    Article  CAS  PubMed  Google Scholar 

  97. Huang, J. T. et al. Interleukin-4-dependent production of PPAR-γ ligands in macrophages by 12/15-lipoxygenase. Nature 400, 378–382 (1999).

    Article  CAS  PubMed  Google Scholar 

  98. Balkwill, F. R. & Mantovani, A. Inflammation and cancer: back to Virchow? Lancet 357, 539–545 (2001).

    Article  CAS  PubMed  Google Scholar 

  99. Kapp, U. et al. Interleukin-13 is secreted by and stimulates the growth of Hodgkin and Reed-Sternberg cells. J. Exp. Med. 189, 1939–1945 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. van den Berg, A., Visser, L. & Poppema, S. High expression of the CC-chemokine TARC in Reed-Sternberg cells. A possible explanation for the characteristic T-cell infiltratein Hodgkin's lymphoma. Am. J. Pathol. 154, 1685–1691 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Schutyser, E. et al. Identification of biologically active chemokine isoforms from ascitic fluid and elevated levels of CCL18/pulmonary and activation-regulated chemokine in ovarian carcinoma. J. Biol. Chem. 277, 24584–24593 (2002).

    Article  CAS  PubMed  Google Scholar 

  102. Lin, E. Y., Nguyen, A. V., Russell, R. G. & Pollard, J. W. Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J. Exp. Med. 193, 727–740 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Nowicki, A. et al. Impaired tumor growth in colony-stimulating factor 1 (CSF-1)-deficient, macrophage-deficient op/op mouse: evidence for a role of CSF-1-dependent macrophages in formation of tumor stroma. Int. J. Cancer 65, 112–119 (1996).

    Article  CAS  PubMed  Google Scholar 

  104. Crowther, M., Brown, N. J., Bishop, E. T. & Lewis, C. E. Microenvironmental influence on macrophage regulation of angiogenesis in wounds and malignant tumors. J. Leukocyte Biol. 70, 478–490 (2001).

    CAS  PubMed  Google Scholar 

  105. Geldhof, A. B. et al. Antagonistic effect of NK cells on alternatively activated monocytes: a contribution of NK cells to CTL generation. Blood 100, 4049–4058 (2002).

    Article  CAS  PubMed  Google Scholar 

  106. Chiaramonte, M. G., Donaldson, D. D., Cheever, A. W. & Wynn, T. A. An IL-13 inhibitor blocks the development of hepatic fibrosis during a T-helper type 2-dominated inflammatory response. J. Clin. Invest. 104, 777–785 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Stacey, M., Lin, H. -H., Gordon, S. & McKnight, A. J. LNB-TM7, a novel group of seven-transmembrane proteins related to family-B G-protein-coupled receptors. Trends Biochem. Sci. 25, 284–289 (2000).

    Article  CAS  PubMed  Google Scholar 

  108. Randolph, G. J. Dendritic-cell migration to lymph nodes: cytokines, chemokines and lipid mediators. Semin. Immunol. 13, 267–274 (2001).

    Article  CAS  PubMed  Google Scholar 

  109. Loots, G. G. et al. Identification of a co-ordinate regulator of interleukins 4, 13 and 5 by cross-species sequence comparisons. Science 288, 136–140 (2000).

    Article  CAS  PubMed  Google Scholar 

  110. Mohrs, M. et al. Deletion of a co-ordinate regulator of type-2 cytokine expression in mice. Nature Immunol. 2, 826–828 (2001).

    Article  CAS  Google Scholar 

  111. Lee, G. R., Fields, P. E. & Flavell, R. A. Regulation of IL-4 gene expression by distal regulatory elements and GATA-3 at the chromatin level. Immunity 14, 447–459 (2001).

    Article  CAS  PubMed  Google Scholar 

  112. Fields, P. E., Kim, S. T. & Flavell, R. A. Cutting edge: changes in histone acetylation at the IL-4 and IFN-γ loci accompany TH1/TH2 differentiation. J. Immunol. 169, 647–650 (2002).

    Article  CAS  PubMed  Google Scholar 

  113. Fallon, P. G. et al. IL-4 induces characteristic TH2 responses even in the combined absence of IL-5, IL-9 and IL-13. Immunity 17, 7–17 (2002).

    Article  CAS  PubMed  Google Scholar 

  114. Brubaker, J. O. & Montaner, L. J. Role of interleukin-13 in innate and adaptive immunity. Cell. Mol. Biol. 47, 637–651 (2001).

    CAS  PubMed  Google Scholar 

  115. Brombacher, F. The role of interleukin-13 in infectious diseases and allergy. BioEssays 22, 646–656 (2000). A comprehensive review of the production of IL-13 and its role in wild-type and gene-knockout animal models.

    Article  CAS  PubMed  Google Scholar 

  116. Donnelly, R. P., Dickensheets, H. & Finbloom, D. S. The interleukin-10 signal-transduction pathway and regulation of gene expression in mononuclear phagocytes. J. Interferon Cytokine Res. 19, 563–573 (1999).

    Article  CAS  PubMed  Google Scholar 

  117. Lang, R., Rutschman, R. L., Greaves, D. R. & Murray, P. J. Autocrine deactivation of macrophages in transgenic mice constitutively overexpressing IL-10 under control of the human CD68 promoter. J. Immunol. 168, 3402–3411 (2002).

    Article  CAS  PubMed  Google Scholar 

  118. Lang, R., Patel, D., Morris, J. J., Rutschman, R. L. & Murray, P. J. Shaping gene expression in activated and resting primary macrophages by IL-10. J. Immunol. 169, 2253–2263 (2002).

    Article  CAS  PubMed  Google Scholar 

  119. East, L. & Isacke, C. M. The mannose-receptor family. Biochem. Biophys. Acta. 1572, 364–386 (2002).

    Article  CAS  PubMed  Google Scholar 

  120. Lee, S. J. et al. Mannose receptor-mediated regulation of serum glycoprotein homeostasis. Science 295, 1898–1901 (2002).

    Article  CAS  PubMed  Google Scholar 

  121. Martinez-Pomares, L. et al. Cell-specific glycoforms of sialoadhesin and CD45 are counter receptors for the cysteine-rich domain of the mannose receptor. J. Biol. Chem. 274, 35211–35218 (1999).

    Article  CAS  PubMed  Google Scholar 

  122. Becker, S. & Daniel, E. G. Antagonistic and additive effects of IL-4 and IFN-γ on human monocytes and macrophages: effects on Fc receptors, HLA-D antigens and superoxide production. Cell. Immunol. 129, 351–362 (1990).

    Article  CAS  PubMed  Google Scholar 

  123. Kristiansen, M. et al. Identification of the haemoglobin scavenger receptor. Nature 409, 198–201 (2001).

    Article  CAS  PubMed  Google Scholar 

  124. Goerdt, S., Walsh, L. J., Murphy, G. F. & Pober, J. S. Identification of a novel high molecular weight protein preferentially expressed by sinusoidal endothelial cells in normal human tissues. J. Cell. Biol. 113, 1425–1437 (1991).

    Article  CAS  PubMed  Google Scholar 

  125. Gratchev, A. et al. Alternatively activated macrophages differentially express fibronectin and its splice variants and the extracellular matrix protein βIG-H3. Scand. J. Immunol. 53, 386–392 (2001).

    Article  CAS  PubMed  Google Scholar 

  126. Kodelja, V. et al. Alternative macrophage activation-associated CC-chemokine 1, a novel structural homologue of macrophage inflammatory protein-1α with a TH2-associated expression pattern. J. Immunol. 160, 1411–1418 (1998).

    CAS  PubMed  Google Scholar 

  127. Kambayashi, T., Jacob, C. O. & Strassmann, G. IL-4 and IL-13 modulate IL-10 release in endotoxin-stimulated murine peritoneal mononuclear phagocytes. Cell. Immunol. 171, 153–158 (1996).

    Article  CAS  PubMed  Google Scholar 

  128. Lee, C. G. et al. Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor-β1. J. Exp. Med. 194, 809–821 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Conrad, D. J., Kuhn, H., Mulkins, M., Highland, E. & Sigal, E. Specific inflammatory cytokines regulate the expression of human monocyte 15-lipoxygenase. Proc. Natl Acad. Sci. USA 89, 217–221 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Work in my laboratory is supported by the Medical Research Council, UK, The Wellcome Trust, the Arthritis Research Campaign and the British Heart Foundation. I thank C. Holt for invaluable help with the preparation of this manuscript, and many colleagues for helpful discussions.

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DATABASES

LocusLink

ApoE

β-glucan receptor

CCL2

CCL3

CCL4

CCL5

CCL17

CCL18

CCL22

CCR1

CCR2

CCR4

CCR5

CD31

CD32

CD47

CXCL1

CXCL2

CXCL9

CXCL10

CXCR1

CXCR2

EMR1

FIZZ1

GATA3

GM-CSF

IDO

IFN-γ

IL-1

IL-3

IL-4

IL-6

IL-9

IL-10

IL-12

IL-13

IL-17

IL-18

IL-25

KIT

mannose receptor

M-CSF

NOS2

PPARγ

PU.1

SOCS3

SR-A

STAT3

STAT6

TGF-β

TNF

VEGF

Ym1

Glossary

CRE–LOX TECHNOLOGY

Cre is a site-specific recombinase that recognizes and binds specific sites known as loxP. Two loxP sites recombine in the presence of Cre, allowing DNA that is cloned between two such sites to be removed by Cre-mediated recombination.

CHROMATIN IMMUNOPRECIPITATION

(ChIP). The use of antibodies specific for transcription factors to precipitate nucleic-acid sequences from chromatin for amplification.

SUPPRESSION SUBTRACTIVE HYBRIDIZATION

A method to isolate unique messenger RNA sequences from paired sources, by subtracting common sequences, for complementary-DNA production.

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Gordon, S. Alternative activation of macrophages. Nat Rev Immunol 3, 23–35 (2003). https://doi.org/10.1038/nri978

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