Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Alveolar macrophages: plasticity in a tissue-specific context

Key Points

  • Alveolar macrophages exist in a complex and unique environment. The ever-changing needs of the lungs mean that the functional and phenotypical plasticity of alveolar macrophages is essential for the appropriate initiation and resolution of lung inflammation.

  • In healthy individuals, alveolar macrophages do not neatly fit into any category using the current macrophage classification system.

  • Alveolar macrophages express a unique range of receptors that regulate their function in the healthy state.

  • Efferocytosis of apoptotic cells and wound repair limit alveolar macrophage responses in the resolution of inflammation. This can lead to long-term consequences, including bacterial superinfection.

  • Important information could be obtained if we increase our understanding of how the threshold of alveolar macrophage activation is set by the varying global microenvironments that are encountered at birth.

Abstract

Alveolar macrophages exist in a unique microenvironment and, despite historical evidence showing that they are in close contact with the respiratory epithelium, have until recently been investigated in isolation. The microenvironment of the airway lumen has a considerable influence on many aspects of alveolar macrophage phenotype, function and turnover. As the lungs adapt to environmental challenges, so too do alveolar macrophages adapt to accommodate the ever-changing needs of the tissue. In this Review, we discuss the unique characteristics of alveolar macrophages, the mechanisms that drive their adaptation and the direct and indirect influences of epithelial cells on them. We also highlight how airway luminal macrophages function as sentinels of a healthy state and how they do not respond in a pro-inflammatory manner to antigens that do not disrupt lung structure. The unique tissue location and function of alveolar macrophages distinguish them from other macrophage populations and suggest that it is important to classify macrophages according to the site that they occupy.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Leukocyte interactions in the healthy lungs.
Figure 2: Negative regulators of alveolar macrophage activation.
Figure 3: The balancing act of macrophage activation.
Figure 4: Altered macrophage regulation after inflammation.

Similar content being viewed by others

References

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

    CAS  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Schulz, C. et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336, 86–90 (2012).

    CAS  PubMed  Google Scholar 

  4. Guilliams, M. et al. Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF. J. Exp. Med. 210, 1977–1992 (2013). This landmark paper describes how the lungs are populated with alveolar macrophages that are derived from foetal monocytes in the first few days after birth.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Schmidt, A. et al. Macrophages in experimental rat lung isografts and allografts: infiltration and proliferation in situ. J. Leukoc. Biol. 81, 186–194 (2007).

    CAS  PubMed  Google Scholar 

  6. 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).

    CAS  PubMed  Google Scholar 

  7. 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 

  8. Hashimoto, D. et al. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38, 792–804 (2013). This paper describes the ability of airway macrophages to self-renew without a contribution from the bone marrow.

    CAS  PubMed  Google Scholar 

  9. Yona, S. et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38, 79–91 (2013).

    CAS  PubMed  Google Scholar 

  10. Ghoneim, H. E., Thomas, P. G. & McCullers, J. A. Depletion of alveolar macrophages during influenza infection facilitates bacterial superinfections. J. Immunol. 191, 1250–1259 (2013).

    CAS  PubMed  Google Scholar 

  11. Worlitzsch, D. et al. Effects of reduced mucus oxygen concentration in airway Pseudomonas infections of cystic fibrosis patients. J. Clin. Invest. 109, 317–325 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Schaible, B., Schaffer, K. & Taylor, C. T. Hypoxia, innate immunity and infection in the lung. Respir. Physiol. Neurobiol. 174, 235–243 (2010).

    CAS  PubMed  Google Scholar 

  13. Cummins, E. P. et al. Prolyl hydroxylase-1 negatively regulates IκB kinase-β, giving insight into hypoxia-induced NFκB activity. Proc. Natl Acad. Sci. USA 103, 18154–18159 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Leonard, M. O. et al. Hypoxia selectively activates the CREB family of transcription factors in the in vivo lung. Am. J. Respir. Crit. Care Med. 178, 977–983 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Goulding, J. et al. Lowering the threshold of lung innate immune cell activation alters susceptibility to secondary bacterial superinfection. J. Infect. Dis. 204, 1086–1094 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Charlson, E. S. et al. Topographical continuity of bacterial populations in the healthy human respiratory tract. Am. J. Respir. Crit. Care Med. 184, 957–963 (2011).

    PubMed  PubMed Central  Google Scholar 

  17. Snelgrove, R. J. et al. A critical function for CD200 in lung immune homeostasis and the severity of influenza infection. Nature Immunol. 9, 1074–1083 (2008). This paper describes the crucial role that epithelial cell expression of CD200 has in regulating airway macrophage function.

    CAS  Google Scholar 

  18. Munger, J. S. et al. The integrin αvβ6 binds and activates latent TGFβ1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 96, 319–328 (1999). This paper suggests the idea that localized activation of TGFβ1 in the lungs is mediated by αvβ6 integrin.

    CAS  PubMed  Google Scholar 

  19. Bonfield, T. L. et al. Normal bronchial epithelial cells constitutively produce the anti-inflammatory cytokine interleukin-10, which is downregulated in cystic fibrosis. Am. J. Respir. Cell. Mol. Biol. 13, 257–261 (1995).

    CAS  PubMed  Google Scholar 

  20. Ely, K. H., Cookenham, T., Roberts, A. D. & Woodland, D. L. Memory T cell populations in the lung airways are maintained by continual recruitment. J. Immunol. 176, 537–543 (2006).

    CAS  PubMed  Google Scholar 

  21. Snelgrove, R. J., Godlee, A. & Hussell, T. Airway immune homeostasis and implications for influenza-induced inflammation. Trends Immunol. 32, 328–334 (2011).

    CAS  PubMed  Google Scholar 

  22. Lipscomb, M. F. et al. Human alveolar macrophages: HLA-DR-positive macrophages that are poor stimulators of a primary mixed leukocyte reaction. J. Immunol. 136, 497–504 (1986).

    CAS  PubMed  Google Scholar 

  23. Lyons, C. R. et al. Inability of human alveolar macrophages to stimulate resting T cells correlates with decreased antigen-specific T cell-macrophage binding. J. Immunol. 137, 1173–1180 (1986).

    CAS  PubMed  Google Scholar 

  24. Toews, G. B. et al. The accessory cell function of human alveolar macrophages in specific T cell proliferation. J. Immunol. 132, 181–186 (1984).

    CAS  PubMed  Google Scholar 

  25. Kirby, A. C., Coles, M. C. & Kaye, P. M. Alveolar macrophages transport pathogens to lung draining lymph nodes. J. Immunol. 183, 1983–1989 (2009).

    CAS  PubMed  Google Scholar 

  26. Blumenthal, R. L. et al. Human alveolar macrophages induce functional inactivation in antigen-specific CD4 T cells. J. Allergy Clin. Immunol. 107, 258–264 (2001).

    CAS  PubMed  Google Scholar 

  27. Holt, P. G. Inhibitory activity of unstimulated alveolar macrophages on T-lymphocyte blastogenic response. Am. Rev. Respir. Dis. 118, 791–793 (1978). This paper describes the changing functions of airway macrophages, from T cell-inhibitory to pro-inflammatory, in the steady state and in the inflamed lungs, respectively.

    CAS  PubMed  Google Scholar 

  28. Hoidal, J. R., Schmeling, D. & Peterson, P. K. Phagocytosis, bacterial killing, and metabolism by purified human lung phagocytes. J. Infect. Dis. 144, 61–71 (1981).

    CAS  PubMed  Google Scholar 

  29. Roth, M. D. & Golub, S. H. Human pulmonary macrophages utilize prostaglandins and transforming growth factor-β1 to suppress lymphocyte activation. J. Leukoc. Biol. 53, 366–371 (1993).

    CAS  PubMed  Google Scholar 

  30. Coleman, M. M. et al. Alveolar macrophages contribute to respiratory tolerance by inducing FoxP3 expression in naive T cells. Am. J. Respir. Cell. Mol. Biol. 48, 773–780 (2013).

    CAS  PubMed  Google Scholar 

  31. Soroosh, P. et al. Lung-resident tissue macrophages generate Foxp3+ regulatory T cells and promote airway tolerance. J. Exp. Med. 210, 775–788 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Kaur, M. et al. T lymphocyte insensitivity to corticosteroids in chronic obstructive pulmonary disease. Respir. Res. 13, 20 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Maus, U. A. et al. Resident alveolar macrophages are replaced by recruited monocytes in response to endotoxin-induced lung inflammation. Am. J. Respir. Cell. Mol. Biol. 35, 227–235 (2006).

    CAS  PubMed  Google Scholar 

  34. Janssen, W. J. et al. Fas determines differential fates of resident and recruited macrophages during resolution of acute lung injury. Am. J. Respir. Crit. Care Med. 184, 547–560 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Hoppstadter, J. et al. Differential cell reaction upon Toll-like receptor 4 and 9 activation in human alveolar and lung interstitial macrophages. Respir. Res. 11, 124 (2010).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  Google Scholar 

  37. Martinez, F. O., Sica, A., Mantovani, A. & Locati, M. Macrophage activation and polarization. Front. Biosci. 13, 453–461 (2008).

    CAS  PubMed  Google Scholar 

  38. Edwards, J. P., Zhang, X., Frauwirth, K. A. & Mosser, D. M. Biochemical and functional characterization of three activated macrophage populations. J. Leukoc. Biol. 80, 1298–1307 (2006).

    CAS  PubMed  Google Scholar 

  39. Mosser, D. M. & Edwards, J. P. Exploring the full spectrum of macrophage activation. Nature Rev. Immunol. 8, 958–969 (2008). This paper describes the extension of M1 and M2 macrophage classification to include a broad range of macrophage functions.

    CAS  Google Scholar 

  40. Shaykhiev, R. et al. Smoking-dependent reprogramming of alveolar macrophage polarization: implication for pathogenesis of chronic obstructive pulmonary disease. J. Immunol. 183, 2867–2883 (2009).

    CAS  PubMed  Google Scholar 

  41. Kim, E. Y. et al. Persistent activation of an innate immune response translates respiratory viral infection into chronic lung disease. Nature Med. 14, 633–640 (2008).

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  43. Pechkovsky, D. V. et al. Alternatively activated alveolar macrophages in pulmonary fibrosis-mediator production and intracellular signal transduction. Clin. Immunol. 137, 89–101 (2010).

    CAS  PubMed  Google Scholar 

  44. Draijer, C., Robbe, P., Boorsma, C. E., Hylkema, M. N. & Melgert, B. N. Characterization of macrophage phenotypes in three murine models of house-dust-mite-induced asthma. Mediators Inflamm. 2013, 632049 (2013).

    PubMed  PubMed Central  Google Scholar 

  45. Zaynagetdinov, R. et al. Identification of myeloid cell subsets in murine lungs using flow cytometry. Am. J. Respir. Cell. Mol. Biol. 49, 180–189 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Malhotra, V., Hogg, N. & Sim, R. B. Ligand binding by the p150,95 antigen of U937 monocytic cells: properties in common with complement receptor type 3 (CR3). Eur. J. Immunol. 16, 1117–1123 (1986).

    CAS  PubMed  Google Scholar 

  47. Guth, A. M. et al. Lung environment determines unique phenotype of alveolar macrophages. Am. J. Physiol. Lung Cell. Mol. Physiol. 296, L936–L946 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Inaba, K. et al. Tissue distribution of the DEC-205 protein that is detected by the monoclonal antibody NLDC-145. I. Expression on dendritic cells and other subsets of mouse leukocytes. Cell. Immunol. 163, 148–156 (1995).

    CAS  PubMed  Google Scholar 

  49. Lahoud, M. H. et al. DEC-205 is a cell surface receptor for CpG oligonucleotides. Proc. Natl Acad. Sci. USA 109, 16270–16275 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Misharin, A. V., Morales-Nebreda, L., Mutlu, G. M., Budinger, G. R. & Perlman, H. Flow cytometric analysis of the macrophages and dendritic cell subsets in the mouse lung. Am. J. Respir. Cell Mol. Biol. 49, 503–510 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Zhang, M. et al. Defining the in vivo function of Siglec-F, a CD33-related Siglec expressed on mouse eosinophils. Blood 109, 4280–4287 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Mao, H. et al. Mechanisms of Siglec-F-induced eosinophil apoptosis: a role for caspases but not for SHP-1 Src kinases, NADPH oxidase or reactive oxygen. PLoS ONE. 8, e68143 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Song, D. J. et al. Anti-Siglec-F antibody reduces allergen-induced eosinophilic inflammation and airway remodeling. J. Immunol. 183, 5333–5341 (2009).

    CAS  PubMed  Google Scholar 

  54. Mayer, A. K., Bartz, H., Fey, F., Schmidt, L. M. & Dalpke, A. H. Airway epithelial cells modify immune responses by inducing an anti-inflammatory microenvironment. Eur. J. Immunol. 38, 1689–1699 (2008).

    CAS  PubMed  Google Scholar 

  55. Wright, G. J. et al. Lymphoid/neuronal cell surface OX2 glycoprotein recognizes a novel receptor on macrophages implicated in the control of their function. Immunity 13, 233–242 (2000).

    CAS  PubMed  Google Scholar 

  56. Koning, N. et al. Expression of the inhibitory CD200 receptor is associated with alternative macrophage activation. J. Innate Immun. 2, 195–200 (2010).

    CAS  PubMed  Google Scholar 

  57. Hatherley, D. & Barclay, A. N. The CD200 and CD200 receptor cell surface proteins interact through their N-terminal immunoglobulin-like domains. Eur. J. Immunol. 34, 1688–1694 (2004).

    CAS  PubMed  Google Scholar 

  58. Jiang-Shieh, Y. F. et al. Distribution and expression of CD200 in the rat respiratory system under normal and endotoxin-induced pathological conditions. J. Anat. 216, 407–416 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Zhang, S., Cherwinski, H., Sedgwick, J. D. & Phillips, J. H. Molecular mechanisms of CD200 inhibition of mast cell activation. J. Immunol. 173, 6786–6793 (2004).

    CAS  PubMed  Google Scholar 

  60. Mihrshahi, R., Barclay, A. N. & Brown, M. H. Essential roles for Dok2 and RasGAP in CD200 receptor-mediated regulation of human myeloid cells. J. Immunol. 183, 4879–4886 (2009).

    CAS  PubMed  Google Scholar 

  61. Mihrshahi, R. & Brown, M. H. Downstream of tyrosine kinase 1 and 2 play opposing roles in CD200 receptor signaling. J. Immunol. 185, 7216–7222 (2010).

    CAS  PubMed  Google Scholar 

  62. Barclay, A. N. Signal regulatory protein-α (SIRPα)/CD47 interaction and function. Curr. Opin. Immunol. 21, 47–52 (2009). This paper highlights the regulatory role of the SIRP family of receptors.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Shultz, L. D., Rajan, T. V. & Greiner, D. L. Severe defects in immunity and hematopoiesis caused by SHP-1 protein-tyrosine-phosphatase deficiency. Trends Biotechnol. 15, 302–307 (1997).

    CAS  PubMed  Google Scholar 

  64. Gardai, S. J. et al. By binding SIRPα or calreticulin/CD91, lung collectins act as dual function surveillance molecules to suppress or enhance inflammation. Cell 115, 13–23 (2003).

    CAS  PubMed  Google Scholar 

  65. Burger, P., Hilarius-Stokman, P., deKorte, D. & van denBerg, T. K. & van Bruggen, R. CD47 functions as a molecular switch for erythrocyte phagocytosis. Blood 119, 5512–5521 (2012).

    CAS  PubMed  Google Scholar 

  66. Oldenborg, P. A. et al. Role of CD47 as a marker of self on red blood cells. Science 288, 2051–2054 (2000).

    CAS  PubMed  Google Scholar 

  67. Legrand, N. et al. Functional CD47/signal regulatory protein alpha (SIRPα) interaction is required for optimal human T− and natural killer- (NK) cell homeostasis in vivo. Proc. Natl Acad. Sci. USA 108, 13224–13229 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Wang, H. et al. Lack of CD47 on nonhematopoietic cells induces split macrophage tolerance to CD47null cells. Proc. Natl Acad. Sci. USA 104, 13744–13749 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. van Beek, E. M., Cochrane, F., Barclay, A. N. & van den Berg, T. K. Signal regulatory proteins in the immune system. J. Immunol. 175, 7781–7787 (2005).

    CAS  PubMed  Google Scholar 

  70. Barclay, A. N. & Brown, M. H. The SIRP family of receptors and immune regulation. Nature Rev. Immunol. 6, 457–464 (2006).

    CAS  Google Scholar 

  71. Gardai, S. J. et al. Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell 123, 321–334 (2005).

    CAS  PubMed  Google Scholar 

  72. Oldenborg, P. A. Role of CD47 in erythroid cells and in autoimmunity. Leuk. Lymphoma 45, 1319–1327 (2004).

    CAS  PubMed  Google Scholar 

  73. Janssen, W. J. et al. Surfactant proteins A and D suppress alveolar macrophage phagocytosis via interaction with SIRPα. Am. J. Respir. Crit. Care Med. 178, 158–167 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Steele, C. et al. Alveolar macrophage-mediated killing of Pneumocystis carinii f. sp. muris involves molecular recognition by the Dectin-1 β-glucan receptor. J. Exp. Med. 198, 1677–1688 (2003). This paper describes the importance of surfactant proteins in the tonic inhibition of alveolar macrophages by SIRPα.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Neese, L. W., Standing, J. E., Olson, E. J., Castro, M. & Limper, A. H. Vitronectin, fibronectin, and gp120 antibody enhance macrophage release of TNFα in response to Pneumocystis carinii. J. Immunol. 152, 4549–4556 (1994).

    CAS  PubMed  Google Scholar 

  76. Zhang, J. et al. Negative regulatory role of mannose receptors on human alveolar macrophage proinflammatory cytokine release in vitro. J. Leukoc. Biol. 78, 665–674 (2005).

    CAS  PubMed  Google Scholar 

  77. Ghosh, S., Gregory, D., Smith, A. & Kobzik, L. MARCO regulates early inflammatory responses against influenza: a useful macrophage function with adverse outcome. Am. J. Respir. Cell. Mol. Biol. 45, 1036–1044 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Gao, X., Dong, Y., Liu, Z. & Niu, B. Silencing of triggering receptor expressed on myeloid cells-2 enhances the inflammatory responses of alveolar macrophages to lipopolysaccharide. Mol. Med. Rep. 7, 921–926 (2013). This paper shows the importance of TREM2 in limiting TLR responses in airway macrophages.

    CAS  PubMed  Google Scholar 

  79. Colonna, M. TREMs in the immune system and beyond. Nature Rev. Immunol. 3, 445–453 (2003). This is an excellent detailed overview of the role of TREM family members in limiting or promoting inflammation.

    CAS  Google Scholar 

  80. Habibzay, M., Saldana, J. I., Goulding, J., Lloyd, C. M. & Hussell, T. Altered regulation of Toll-like receptor responses impairs antibacterial immunity in the allergic lung. Mucosal. Immunol. 5, 524–534 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Khoor, A., Gray, M. E., Hull, W. M., Whitsett, J. A. & Stahlman, M. T. Developmental expression of SP-A and SP-A mRNA in the proximal and distal respiratory epithelium in the human fetus and newborn. J. Histochem. Cytochem. 41, 1311–1319 (1993).

    CAS  PubMed  Google Scholar 

  82. Watford, W. T., Wright, J. R., Hester, C. G., Jiang, H. & Frank, M. M. Surfactant protein A regulates complement activation. J. Immunol. 167, 6593–6600 (2001).

    CAS  PubMed  Google Scholar 

  83. Yamada, C. et al. Surfactant protein A directly interacts with TLR4 and MD-2 and regulates inflammatory cellular response. Importance of supratrimeric oligomerization. J. Biol. Chem. 281, 21771–21780 (2006).

    CAS  PubMed  Google Scholar 

  84. Sano, H. et al. Pulmonary surfactant protein A modulates the cellular response to smooth and rough lipopolysaccharides by interaction with CD14. J. Immunol. 163, 387–395 (1999).

    CAS  PubMed  Google Scholar 

  85. Haczku, A. Protective role of the lung collectins surfactant protein A and surfactant protein D in airway inflammation. J. Allergy Clin. Immunol. 122, 861–879 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Morris, D. G. et al. Loss of integrin αvβ6-mediated TGFβ activation causes Mmp12-dependent emphysema. Nature 422, 169–173 (2003).

    CAS  PubMed  Google Scholar 

  87. Markowitz, S. et al. Inactivation of the type II TGFβ receptor in colon cancer cells with microsatellite instability. Science 268, 1336–1338 (1995).

    CAS  PubMed  Google Scholar 

  88. Derynck, R. & Zhang, Y. E. Smad-dependent and Smad-independent pathways in TGFβ family signalling. Nature 425, 577–584 (2003).

    CAS  PubMed  Google Scholar 

  89. Rojas, A., Padidam, M., Cress, D. & Grady, W. M. TGFβ receptor levels regulate the specificity of signaling pathway activation and biological effects of TGFβ. Biochim. Biophys. Acta 1793, 1165–1173 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Coker, R. K. et al. Diverse cellular TGFβ1 and TGFβ3 gene expression in normal human and murine lung. Eur. Respir. J. 9, 2501–2507 (1996).

    CAS  PubMed  Google Scholar 

  91. Yehualaeshet, T. et al. Activation of rat alveolar macrophage-derived latent transforming growth factor-β1 by plasmin requires interaction with thrombospondin-1 and its cell surface receptor, CD36. Am. J. Pathol. 155, 841–851 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Fernandez, S., Jose, P., Avdiushko, M. G., Kaplan, A. M. & Cohen, D. A. Inhibition of IL-10 receptor function in alveolar macrophages by Toll-like receptor agonists. J. Immunol. 172, 2613–2620 (2004).

    CAS  PubMed  Google Scholar 

  93. Murray, P. J. Understanding and exploiting the endogenous interleukin-10/STAT3-mediated anti-inflammatory response. Curr. Opin. Pharmacol. 6, 379–386 (2006).

    CAS  PubMed  Google Scholar 

  94. Murray, P. J. The primary mechanism of the IL-10-regulated antiinflammatory response is to selectively inhibit transcription. Proc. Natl Acad. Sci. USA 102, 8686–8691 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Curtale, G. et al. Negative regulation of Toll-like receptor 4 signaling by IL-10-dependent microRNA-146b. Proc. Natl Acad. Sci. USA 110, 11499–11504 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Lim, S. et al. Differential expression of IL-10 receptor by epithelial cells and alveolar macrophages. Allergy 59, 505–514 (2004).

    CAS  PubMed  Google Scholar 

  97. Chen, B. D., Mueller, M. & Chou, T. H. Role of granulocyte/macrophage colony-stimulating factor in the regulation of murine alveolar macrophage proliferation and differentiation. J. Immunol. 141, 139–144 (1988).

    CAS  PubMed  Google Scholar 

  98. Higgins, D. M. et al. Relative levels of M-CSF and GM-CSF influence the specific generation of macrophage populations during infection with Mycobacterium tuberculosis. J. Immunol. 180, 4892–4900 (2008).

    CAS  PubMed  Google Scholar 

  99. Trapnell, B. C. & Whitsett, J. A. GM-CSF regulates pulmonary surfactant homeostasis and alveolar macrophage-mediated innate host defense. Annu. Rev. Physiol. 64, 775–802 (2002).

    CAS  PubMed  Google Scholar 

  100. Trapnell, B. C., Carey, B. C., Uchida, K. & Suzuki, T. Pulmonary alveolar proteinosis, a primary immunodeficiency of impaired GM-CSF stimulation of macrophages. Curr. Opin. Immunol. 21, 514–521 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Gautier, E. L. 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).

    CAS  Google Scholar 

  102. Malur, A. et al. Restoration of PPARγ reverses lipid accumulation in alveolar macrophages of GM-CSF knockout mice. Am. J. Physiol. Lung Cell. Mol. Physiol. 300, L73–L80 (2011).

    CAS  PubMed  Google Scholar 

  103. Gautier, E. L. et al. Systemic analysis of PPARγ in mouse macrophage populations reveals marked diversity in expression with critical roles in resolution of inflammation and airway immunity. J. Immunol. 189, 2614–2624 (2012).

    CAS  PubMed  Google Scholar 

  104. Krysko, D. V., D'Herde, K. & Vandenabeele, P. Clearance of apoptotic and necrotic cells and its immunological consequences. Apoptosis 11, 1709–1726 (2006).

    PubMed  Google Scholar 

  105. Lemke, G. & Rothlin, C. V. Immunobiology of the TAM receptors. Nature Rev. Immunol. 8, 327–336 (2008). This is a detailed review of the role of TAM receptors in the regulation of innate immunity.

    CAS  Google Scholar 

  106. Klesney-Tait, J., Turnbull, I. R. & Colonna, M. The TREM receptor family and signal integration. Nature Immunol. 7, 1266–1273 (2006). This paper is an overview of TREM ligands and their roles in inflammation.

    CAS  Google Scholar 

  107. Powers, K. A. et al. Oxidative stress generated by hemorrhagic shock recruits Toll-like receptor 4 to the plasma membrane in macrophages. J. Exp. Med. 203, 1951–1961 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Maris, N. A. et al. Toll-like receptor mRNA levels in alveolar macrophages after inhalation of endotoxin. Eur. Respir. J. 28, 622–626 (2006).

    CAS  PubMed  Google Scholar 

  109. Oshikawa, K. & Sugiyama, Y. Regulation of toll-like receptor 2 and 4 gene expression in murine alveolar macrophages. Exp. Lung Res. 29, 401–412 (2003).

    CAS  PubMed  Google Scholar 

  110. Bilyk, N. & Holt, P. G. Cytokine modulation of the immunosuppressive phenotype of pulmonary alveolar macrophage populations. Immunology 86, 231–237 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Lohmann-Matthes, M. L., Steinmuller, C. & Franke-Ullmann, G. Pulmonary macrophages. Eur. Respir. J. 7, 1678–1689 (1994).

    CAS  PubMed  Google Scholar 

  112. Steinmuller, C., Franke-Ullmann, G., Lohmann-Matthes, M. L. & Emmendorffer, A. Local activation of nonspecific defense against a respiratory model infection by application of interferon-γ: comparison between rat alveolar and interstitial lung macrophages. Am. J. Respir. Cell. Mol. Biol. 22, 481–490 (2000).

    CAS  PubMed  Google Scholar 

  113. Naessens, T. et al. Innate imprinting of murine resident alveolar macrophages by allergic bronchial inflammation causes a switch from hypoinflammatory to hyperinflammatory reactivity. Am. J. Pathol. 181, 174–184 (2012).

    CAS  PubMed  Google Scholar 

  114. Hogner, K. et al. Macrophage-expressed IFNβ contributes to apoptotic alveolar epithelial cell injury in severe influenza virus pneumonia. PLoS. Pathog. 9, e1003188 (2013).

    PubMed  PubMed Central  Google Scholar 

  115. Herold, S. et al. Lung epithelial apoptosis in influenza virus pneumonia: the role of macrophage-expressed TNF-related apoptosis-inducing ligand. J. Exp. Med. 205, 3065–3077 (2008). This study highlights the damaging influence of recruited airway macrophages in epithelial cell apoptosis.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Bem, R. A. et al. Potential role of soluble TRAIL in epithelial injury in children with severe RSV infection. Am. J. Respir. Cell. Mol. Biol. 42, 697–705 (2010).

    CAS  PubMed  Google Scholar 

  117. Kim, H. M. et al. Alveolar macrophages are indispensable for controlling influenza viruses in lungs of pigs. J. Virol. 82, 4265–4274 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Tate, M. D., Pickett, D. L., van, R. N., Brooks, A. G. & Reading, P. C. Critical role of airway macrophages in modulating disease severity during influenza virus infection of mice. J. Virol. 84, 7569–7580 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Tumpey, T. M. et al. Pathogenicity of influenza viruses with genes from the 1918 pandemic virus: functional roles of alveolar macrophages and neutrophils in limiting virus replication and mortality in mice. J. Virol. 79, 14933–14944 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Maelfait, J. et al. A20 (Tnfaip3) deficiency in myeloid cells protects against influenza A virus infection. PLoS. Pathog. 8, e1002570 (2012). This paper highlights an important idea: that the induction of early increased inflammation, by removing the ubiquitin-editing protein A20, is beneficial during influenza infection.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Alber, A., Howie, S. E., Wallace, W. A. & Hirani, N. The role of macrophages in healing the wounded lung. Int. J. Exp. Pathol. 93, 243–251 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. He, C., Ryan, A. J., Murthy, S. & Carter, A. B. Accelerated development of pulmonary fibrosis via Cu, Zn-superoxide dismutase-induced alternative activation of macrophages. J. Biol. Chem. 288, 20745–20757 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Gordon, S. & Martinez, F. O. Alternative activation of macrophages: mechanism and functions. Immunity. 32, 593–604 (2010).

    CAS  PubMed  Google Scholar 

  124. Rouhani, F. N. et al. Alveolar macrophage dysregulation in Hermansky–Pudlak syndrome type 1. Am. J. Respir. Crit. Care Med. 180, 1114–1121 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Prieto, J. et al. Increased interleukin-13 mRNA expression in bronchoalveolar lavage cells of atopic patients with mild asthma after repeated low-dose allergen provocations. Respir. Med. 94, 806–814 (2000).

    CAS  PubMed  Google Scholar 

  126. Magnan, A., van, P. D., Bongrand, P. & Vervloet, D. Alveolar macrophage interleukin (IL)-10 and IL-12 production in atopic asthma. Allergy 53, 1092–1095 (1998).

    CAS  PubMed  Google Scholar 

  127. Gibbons, M. A. et al. Ly6Chi monocytes direct alternatively activated profibrotic macrophage regulation of lung fibrosis. Am. J. Respir. Crit. Care Med. 184, 569–581 (2011).

    CAS  PubMed  Google Scholar 

  128. Dhariwal, K. R., Shirvan, M. & Levine, M. Ascorbic acid regeneration in chromaffin granules. In situ kinetics. J. Biol. Chem. 266, 5384–5387 (1991).

    CAS  PubMed  Google Scholar 

  129. Sun, K. & Metzger, D. W. Inhibition of pulmonary antibacterial defense by interferon-gamma during recovery from influenza infection. Nature Med. 14, 558–564 (2008).

    CAS  PubMed  Google Scholar 

  130. Didierlaurent, A. et al. Sustained desensitization to bacterial Toll-like receptor ligands after resolution of respiratory influenza infection. J. Exp. Med. 205, 323–329 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. van der Sluijs, K. F. et al. IL-10 is an important mediator of the enhanced susceptibility to pneumococcal pneumonia after influenza infection. J. Immunol. 172, 7603–7609 (2004).

    CAS  PubMed  Google Scholar 

  132. Tokairin, Y. et al. Enhanced immediate inflammatory response to Streptococcus pneumoniae in the lungs of mice with pulmonary emphysema. Respirology. 13, 324–332 (2008).

    PubMed  Google Scholar 

  133. Droemann, D. et al. Toll-like receptor 2 expression is decreased on alveolar macrophages in cigarette smokers and COPD patients. Respir. Res. 6, 68 (2005).

    PubMed  PubMed Central  Google Scholar 

  134. Prescott, S. L. Effects of early cigarette smoke exposure on early immune development and respiratory disease. Paediatr. Respir. Rev. 9, 3–9 (2008).

    PubMed  Google Scholar 

  135. Wang, J., Barke, R. A., Charboneau, R., Schwendener, R. & Roy, S. Morphine induces defects in early response of alveolar macrophages to Streptococcus pneumoniae by modulating TLR9–NF-κB signaling. J. Immunol. 180, 3594–3600 (2008).

    CAS  PubMed  Google Scholar 

  136. Lievense, L. A., Bezemer, K., Aerts, J. G. & Hegmans, J. P. Tumor-associated macrophages in thoracic malignancies. Lung Cancer 80, 256–262 (2013).

    CAS  PubMed  Google Scholar 

  137. Iverson, A. R. et al. Influenza virus primes mice for pneumonia from Staphylococcus aureus. J. Infect. Dis. 203, 880–888 (2011).

    PubMed  PubMed Central  Google Scholar 

  138. McCullers, J. A. et al. Influenza enhances susceptibility to natural acquisition of and disease due to Streptococcus pneumoniae in ferrets. J. Infect. Dis. 202, 1287–1295 (2010).

    PubMed  Google Scholar 

  139. Habibzay, M., Weiss, G. & Hussell, T. Bacterial superinfection following lung inflammatory disorders. Future. Microbiol. 8, 247–256 (2013).

    CAS  PubMed  Google Scholar 

  140. Decramer, M., Janssens, W. & Miravitlles, M. Chronic obstructive pulmonary disease. Lancet 379, 1341–1351 (2012).

    PubMed  PubMed Central  Google Scholar 

  141. Jackson, D. J., Sykes, A., Mallia, P. & Johnston, S. L. Asthma exacerbations: origin, effect, and prevention. J. Allergy Clin. Immunol. 128, 1165–1174 (2011).

    PubMed  PubMed Central  Google Scholar 

  142. Walzl, G., Tafuro, S., Moss, P., Openshaw, P. J. & Hussell, T. Influenza virus lung infection protects from respiratory syncytial virus-induced immunopathology. J. Exp. Med. 192, 1317–1326 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Kasahara, K. et al. Intranasal priming of newborn mice with microbial extracts increases opsonic factors and mature CD11c+ cells in the airway. Am. J. Physiol. Lung Cell. Mol. Physiol. 303, L834–L843 (2012). This study highlights that the correct 'education' of alveolar macrophages at birth has long-term beneficial consequences.

    CAS  PubMed  Google Scholar 

  144. Kurkjian, C. et al. Alveolar macrophages in neonatal mice are inherently unresponsive to Pneumocystis murina infection. Infect. Immun. 80, 2835–2846 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. von Garnier, C. et al. Allergic airways disease develops after an increase in allergen capture and processing in the airway mucosa. J. Immunol. 179, 5748–5759 (2007).

    CAS  PubMed  Google Scholar 

  146. Wang, J. Y. & Reid, K. B. The immunoregulatory roles of lung surfactant collectins SP-A, and SP-D, in allergen-induced airway inflammation. Immunobiology 212, 417–425 (2007).

    CAS  PubMed  Google Scholar 

  147. Poulter, L. W., Janossy, G., Power, C., Sreenan, S. & Burke, C. Immunological/physiological relationships in asthma: potential regulation by lung macrophages. Immunol. Today 15, 258–261 (1994).

    CAS  PubMed  Google Scholar 

  148. Wissinger, E., Goulding, J. & Hussell, T. Immune homeostasis in the respiratory tract and its impact on heterologous infection. Semin. Immunol. 21, 147–155 (2009).

    CAS  PubMed  Google Scholar 

  149. Brown, S. D. et al. Airway TGFβ1 and oxidant stress in children with severe asthma: association with airflow limitation. J. Allergy Clin. Immunol. 129, 388–396. e1–e8 (2012).

    CAS  PubMed  Google Scholar 

  150. Fitzpatrick, A. M., Teague, W. G., Burwell, L., Brown, M. S. & Brown, L. A. Glutathione oxidation is associated with airway macrophage functional impairment in children with severe asthma. Pediatr. Res. 69, 154–159 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Fitzpatrick, A. M., Higgins, M., Holguin, F., Brown, L. A. & Teague, W. G. The molecular phenotype of severe asthma in children. J. Allergy Clin. Immunol. 125, 851–857 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Fitzpatrick, A. M., Holguin, F., Teague, W. G. & Brown, L. A. Alveolar macrophage phagocytosis is impaired in children with poorly controlled asthma. J. Allergy Clin. Immunol. 121, 1372–1378. e3 (2008). This paper provides clinical evidence of the defective phagocytosis and increased apoptosis of alveolar macrophages that occurs in children with asthma.

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Lemanske, R. F. Jr. Inflammation in childhood asthma and other wheezing disorders. Pediatrics 109, 368–372 (2002).

    PubMed  Google Scholar 

  154. Pappas, K., Papaioannou, A. I., Kostikas, K. & Tzanakis, N. The role of macrophages in obstructive airways disease: Chronic obstructive pulmonary disease and asthma. Cytokine 64, 613–625 (2013).

    CAS  PubMed  Google Scholar 

  155. Burastero, S. E. et al. Increased expression of the CD80 accessory molecule by alveolar macrophages in asthmatic subjects and its functional involvement in allergen presentation to autologous TH2 lymphocytes. J. Allergy Clin. Immunol. 103, 1136–1142 (1999).

    CAS  PubMed  Google Scholar 

  156. Nicod, L. P. & Isler, P. Alveolar macrophages in sarcoidosis coexpress high levels of CD86 (B7.2), CD40, and CD30L. Am. J. Respir. Cell. Mol. Biol. 17, 91–96 (1997).

    CAS  PubMed  Google Scholar 

  157. Dobbs, L. G. & Johnson, M. D. Alveolar epithelial transport in the adult lung. Respir. Physiol. Neurobiol. 159, 283–300 (2007).

    CAS  PubMed  Google Scholar 

  158. Tam, A., Wadsworth, S., Dorscheid, D., Man, S. F. & Sin, D. D. The airway epithelium: more than just a structural barrier. Ther. Adv. Respir. Dis. 5, 255–273 (2011).

    PubMed  Google Scholar 

  159. Wang, Y. et al. A critical role of activin A in maturation of mouse peritoneal macrophages in vitro and in vivo. Cell Mol. Immunol. 6, 387–392 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  161. Liu, G. et al. Phenotypic and functional switch of macrophages induced by regulatory CD4+CD25+ T cells in mice. Immunol. Cell Biol. 89, 130–142 (2011).

    CAS  PubMed  Google Scholar 

  162. Feng, Y. H. & Mao, H. Expression and preliminary functional analysis of Siglec-F on mouse macrophages. J. Zhejiang Univ. Sci. B 13, 386–394 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors would like to thank M. Exley for his critical reading of the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Tracy Hussell.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

M1 macrophages

M1, or classically activated, macrophages are induced by Toll-like receptor signalling and interferon-γ. They have enhanced antimicrobial properties and secrete pro-inflammatory cytokines such as interleukin-1 (IL-1), IL-6, IL-12, IL-23 and tumour necrosis factor (TNF). They can also express CXC-chemokine ligand 9 (CXCL9), CXCL10, CXCL11 and CC-chemokine ligand 5 (CCL5).

M2 macrophages

M2, or alternatively activated, macrophages are generally induced by interleukin-4 (IL-4) and IL-13, although various M2-like subtypes have been described. These cells contribute to wound healing, are anti-inflammatory and typically express the mannose receptor (also known as CD206), the tyrosine protein kinase MER, growth arrest-specific protein 7 (GAS7), CD163, arginase and tumour necrosis factor-β (TGFβ).

CD200 receptor

(CD200R). The CD200R limits inflammatory macrophage responses by activating RAS GTPase-activating protein (RASGAP), which inhibits the extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK) and JUN N-terminal kinase (JNK) signalling pathways. CD200, the ligand for the CD200R, is found on bronchial and type II alveolar epithelium and on some T cells.

Type II alveolar epithelial cells

Unlike their type I structural counterparts, type II alveolar epithelial cells are involved in airway innate immunity; they secrete pulmonary surfactant-associated proteins and cytokines, and recognize pathogens through Toll-like receptors. They also express ligands, such as CD200, for macrophage regulatory receptors.

Type I alveolar epithelial cells

Type I alveolar epithelial cells make up as much as 98% of the total surface area of the lungs. They have a large surface area and are very thin to facilitate gas exchange between the alveoli and the underlying capillaries.

Efferocytosis

The cell-mediated engulfment and clearance of apoptotic cells, which is similar to phagocytosis. This process is mediated by bridging molecules and cell surface receptors such as the TAM (TYRO3, AXL and MER) receptor family. Efferocytosis typically induces anti-inflammatory signalling pathways within the engulfing phagocyte.

TAM receptor family

Made up of TYRO3, AXL and MER receptor tyrosine kinases. These receptors promote efferocytosis by recognizing externalized phosphatidylserine expressed on the surface of apoptotic cells via the bridging molecules growth arrest-specific protein 6 (GAS6) and protein S.

Myeloid-derived suppressor cells

(MDSCs). A group of immature CD11b+GR1+ cells that include precursors of macrophages, granulocytes, dendritic cells and myeloid cells. These cells are produced in response to various tumour-derived cytokines and have been shown to inhibit tumour-specific immune responses.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hussell, T., Bell, T. Alveolar macrophages: plasticity in a tissue-specific context. Nat Rev Immunol 14, 81–93 (2014). https://doi.org/10.1038/nri3600

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri3600

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing