Semin Respir Crit Care Med 2004; 25(1): 21-31
DOI: 10.1055/s-2004-822302
Copyright © 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Macrophages in Innate and Acquired Immunity

Homer L. Twigg1  III 
  • 1Division of Pulmonary and Critical Care, Indiana University Medical Center, Indianapolis, Indiana
Further Information

Publication History

Publication Date:
12 March 2004 (online)

Alveolar macrophages play a central role in pulmonary host defense. When foreign particles or pathogens enter the respiratory tract, constitutively present innate host defenses attempt to clear the challenge. Alveolar macrophage phagocytosis of foreign material is a critical component of this response, as is secretion of inflammatory mediators designed to combat invading pathogens. If the pathogenic burden is too large and overwhelms innate immunity, then acquired immune responses are initiated resulting in the generation of antigen-specific cellular and humoral immunity. In response to evolutionary pressures to minimize unnecessary inflammation in the lower respiratory tract, alveolar macrophages are generally poor accessory cells in the initiation of specific immunity. However, in many circumstances, especially those associated with cellular activation, alveolar macrophages can play an important role in the generation and expansion of pulmonary immune responses. This review discusses the role of alveolar macrophages in innate and acquired pulmonary host defense.

REFERENCES

  • 1 Thomas E, Ramberg R, Sale G. Direct evidence for a bone marrow origin of the alveolar macrophages in man.  Science. 1976;  192 1016-1080
  • 2 Bitterman P G, Saltzman L E, Adelberg S, Ferrans V J, Crystal R G. Alveolar macrophage replication: one mechanism for the expansion of the mononuclear phagocytes population in the chronically inflamed lung.  J Clin Invest. 1984;  74 460-469
  • 3 Spiteri M A, Clarke S W, Poulter L W. Isolation of phenotypically and functionally distinct macrophage subpopulations from human bronchoalveolar lavage.  Eur Respir J. 1992;  5 717-726
  • 4 Kradin R L, Sakamoto H, Preffer F I, Dombkowski D, Springer K M, Leary C P. Accumulation of macrophages with dendritic cell characteristics in the pulmonary response to Listeria .  Am J Respir Crit Care Med. 2000;  161 535-542
  • 5 Bell D, Young J W, Banchereau J. Dendritic cells.  Adv Immunol. 1999;  72 255-324
  • 6 Lee P T, Holt P G, McWilliam A S. Failure of MHC class II expression in neonatal alveolar macrophages: potential role of class II transactivator.  Eur J Immunol. 2001;  31 2347-2356
  • 7 Grigg J, Riedler J, Robertson C F, Boyle W, Uren S. Alveolar macrophage immaturity in infants and young children.  Eur Respir J. 1999;  14 1198-1205
  • 8 Lee P T, Holt P G, McWilliam A S. Role of alveolar macrophages in innate immunity in neonates: evidence for selective lipopolysaccharide binding protein production by rat neonatal alveolar macrophages.  Am J Respir Cell Mol Biol. 2000;  23 652-661
  • 9 Zissel G, Schlaak M, Muller-Quernheim J. Age-related decrease in accessory cell function of human alveolar macrophages.  J Investig Med. 1999;  47 51-56
  • 10 Corsini E, Viviani B, Lucchi L, Marinovich M, Racchi M, Galli C L. Ontogenesis of protein kinase C βII and its anchoring protein RACK1 in the maturation of alveolar macrophage functional responses.  Immunol Lett. 2001;  76 89-93
  • 11 Glasgow J E, Farrell B E, Fisher E S, Lauffenburger D A, Daniele R P. The motile response of alveolar macrophages.  Am Rev Respir Dis. 1989;  139 320-329
  • 12 Van Oss C J. Phagocytosis: an overview.  Methods Enzymol. 1986;  132 3-15
  • 13 O'Brien A D, Standiford T J, Christensen P J, Wilcoxen S E, Paine R. Chemotaxix of alveolar macrophages in response to signals derived from alveolar epithelial cells.  J Lab Clin Med. 1998;  131 417-424
  • 14 Wright J R, Youmas D C. Pulmonary surfactant protein A stimulates chemotaxis of alveolar macrophages.  Am J Physiol. 1993;  264(Lung Cell Mol Physiol) L338-L344
  • 15 Gordon S, Perry V H, Rabinowitz S, Chung L P, Rosen H. Plasma membrane receptors of the mononuclear phagocyte system.  J Cell Sci. 1988;  9(suppl) 1-26
  • 16 Kobzik L. Lung macrophage uptake of unopsonized environmental particulates: role of scavenger receptors.  J Immunol. 1995;  155 367-376
  • 17 van Crevel R, Ottenhoff T HM, van der Meer J WM. Innate immunity to Mycobacterium tuberculosis .  Clin Microbiol Rev. 2002;  15 294-309
  • 18 Pasula R, Wright J R, Kachel D L, Martin II W J. Surfactant protein A suppresses reactive nitrogen intermediates by alveolar macrophages in response to Mycobacterium tuberculosis .  J Clin Invest. 1999;  103 483-490
  • 19 Downing J F, Pasula R, Wright J R, Twigg H L, Martin II W J. Surfactant protein A promotes attachment of Mycobacterium tuberculosis to alveolar macrophages during infection with human immunodeficiency virus.  Proc Natl Acad Sci USA. 1995;  92 4848-4852
  • 20 Schagat T L, Wofford J A, Wright J R. Surfactant protein A enhances alveolar macrophage phagocytosis of apoptotic neutrophils.  J Immunol. 2001;  166 2727-2733
  • 21 Hu B, Sonstein J, Christensen P J, Punturieri A, Curtis J L. Deficient in vitro and in vivo phagocytosis of apoptotic T cells by resident murine alveolar macrophages.  J Immunol. 2000;  165 2124-2133
  • 22 Aggeler J, Werb Z. Initial events during phagocytosis by macrophages viewed from outside and inside the cell: membrane-particle interactions and clathrin.  J Cell Biol. 1982;  94 613-623
  • 23 Greenberg S, El Khoury J, Di Virgilio F, Kaplan E M, Silverstein S C. Ca2+-independent F-actin assembly and disassembly during Fc receptor-mediated phagocytosis in mouse macrophages.  J Cell Biol. 1991;  113 757-767
  • 24 Nathan C F. Secretion of oxygen intermediates; role in effector functions of activated macrophages.  Fed Proc. 1982;  41 2206-2211
  • 25 Liew F Y, Cos F EG. Nonspecific defence mechanism: the role of nitric oxide.  Immunol Today. 1991;  12 A17-A21
  • 26 Albina J E. On the expression of nitric oxide synthase by human macrophages. Why no NO.  J Leukoc Biol. 1995;  58 643-649
  • 27 Lekstrom-Himes J A, Gallin J I. Immunodeficiency diseases caused by defects in phagocytes.  N Engl J Med. 2000;  343 1703-1714
  • 28 Flynn J L, Chan J, Triebold K J, Dalton D K, Stewart T A, Bloom B R. An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection.  J Exp Med. 1993;  178 2249-2254
  • 29 Orme I M, Cooper A M. Cytokine/chemokine cascades in immunity to tuberculosis.  Immunol Today. 1999;  20 307-312
  • 30 Heldwein K A, Fenton M J. The role of Toll-like receptors in immunity against mycobacterial infection.  Microbes Infect. 2002;  4 937-944
  • 31 Keane J, Remold H G, Kornfeld H. Virulent Mycobacterium tuberculosis strains evade apoptosis of infected alveolar macrophages.  J Immunol. 2000;  164 2016-2020
  • 32 Mancuso P, Standiford T J, Marshall T, Peters-Golden M. 5-Lipoxygenase reaction products modulate alveolar macrophage phagocytosis of Klebsiella pneumoniae .  Infect Immun. 1998;  66 5140-5146
  • 33 Peters-Golden M, Coffey M. Role of leukotrienes in antimicrobial defense of the lung.  J Lab Clin Med. 1998;  132 251-257
  • 34 Coffey M J, Phare S M, Peters-Golden M. Prolonged exposure to lipopolysaccharide inhibits macrophage 5-lipoxygenase metabolism via induction of nitric oxide synthesis.  J Immunol. 2000;  165 3592-3598
  • 35 Rich E A, Panuska J R, Wallis R S, Wolf C B, Leonard M L, Ellner J J. Dyscoordinate expression of tumor necrosis factor-alpha by human blood monocytes and alveolar macrophages.  Am Rev Respir Dis. 1989;  139 1010-1016
  • 36 Iwamoto G K, Monick M M, Burmeister L F, Hunninghake G W. Interleukin 1 release by human alveolar macrophages and blood monocytes.  Am J Physiol. 1989;  256(Cell Physiol 25) C1012-C1015
  • 37 Toossi Z, Hirsch C S, Hamilton B P, Knuth C K, Friedlander M A, Rich E A. Decreased production TGF-beta 1 by human alveolar macrophages compared with blood monocytes.  J Immunol. 1996;  156 3461-3468
  • 38 Moore S A, Strieter R M, Rolfe M W, Standiford T J, Burdick M D, Kunkel S L. Expression and regulation of human alveolar macrophage-derived interleukin-1 receptor antagonist.  Am J Respir Cell Mol Biol. 1992;  6 569-575
  • 39 Martinet Y, Yamauchi K, Crystal R G. Differential expression of tumor necrosis factor/cachectin gene by blood and lung mononuclear phagocytes.  Am Rev Respir Dis. 1988;  138 659-665
  • 40 Strieter R M, Remick D G, Lynch J P et al.. Differential regulation of tumor necrosis factor-alpha in human alveolar macrophages and peripheral blood monocytes: a cellular and molecular analysis.  Am J Respir Cell Mol Biol. 1989;  1 57-63
  • 41 Standiford T J, Kunkel S L, Liebler J M, Burdick M D, Gilbert A R, Strieter R M. Gene expression of macrophage inflammatory protein-1α from human blood monocytes and alveolar macrophages is inhibited by interleukin-4.  Am J Respir Cell Mol Biol. 1993;  9 192-198
  • 42 Salez L, Balloy V, van Rooijen N et al.. Surfactant protein A suppresses lipopolysaccharide-induced IL-10 production by murine macrophages.  J Immunol. 2001;  166 6376-6382
  • 43 Soliman D M, Twigg H L. Cigarette smoking decreases bioactive interleukin-6 secretion by alveolar macrophages.  Am J Physiol. 1992;  263(Lung Cell Mol Physiol) L471-L478
  • 44 McRea K A, Ensor J E, Nall K, Bleecker E R, Hasday J D. Altered cytokine regulation in the lungs of cigarette smokers.  Am J Respir Crit Care Med. 1994;  150 696-703
  • 45 Standiford T J, Huffnagle G B. Cytokines in host defense against pneumonia.  J Investig Med. 1997;  6 335-345
  • 46 Martin T R. Overview of cytokine networks in lung injury. In: Pratter MR, Nelson S Cytokines and Pulmonary Infection Part II: The Role of Cytokines in Systemic and Pulmonary Medicine. ATS Continuing Education Monograph Series: New York, NY; American Lung Association 1997: 19-28
  • 47 Weissler J C, Lipscomb M F, Lem V M, Toews G B. Tumor killing by human alveolar macrophages and blood monocytes.  Am Rev Respir Dis. 1986;  134 532-537
  • 48 Imaizumi K, Kawabe T, Ichiyama S et al.. Enhancement of tumoricidal activity of alveolar macrophages via CD40-CD40 ligand interaction.  Am J Physiol. 1999;  277 L49-L57
  • 49 Sauty A, Manuel J, Philippeaux M, Leuenberger P. Cytostatic activity of alveolar macrophages from smokers and nonsmokers: role of interleukin-1B, interleukin-6, and tumor necrosis factor-α.  Am J Respir Cell Mol Biol. 1994;  11 631-637
  • 50 Lauzon W, Lemaire I. Alveolar macrophage inhibition of lung-associated NK activity: involvement of prostaglandins and transforming growth factor-B1 .  Exp Lung Res. 1994;  20 331-349
  • 51 Kaltreider H B, Curtis J L, Arraj S M. The mechanism of appearance of specific antibody-forming cells in the lungs of inbred mice after imunization with sheep erythrocytes intratracheally.  Am Rev Respir Dis. 1987;  135 87-92
  • 52 Curtis J L, Kaltreider H B. Characterization of bronchoalveolar lymphocytes during a specific antibody-forming cell response in the lungs of mice.  Am Rev Respir Dis. 1989;  139 393-400
  • 53 Toews G B, Vial W C, Dunn M M et al.. The accessory cell function of human alveolar macrophages in specific T cell proliferation.  J Immunol. 1984;  132 181-186
  • 54 Lipscomb M F, Lyons C R, Nunez G et al.. Human alveolar macrophages: HLA-DR-positive macrophages that are poor stimulators of a primary mixed leukocyte reaction.  J Immunol. 1986;  136 497-504
  • 55 Lyons C R, Ball E J, Toews G B, Weissler J C, Stastny P, Lipscomb M F. Inability of human alveolar macrophages to stimulate resting T cells correlates with decreased antigen-specific T cell-macrophage binding.  J Immunol. 1986;  137 1173-1180
  • 56 Holt P G, Oliver J, Bilyk N et al.. Downregulation of the antigen-presenting cell functions(s) of pulmonary dendritic cells in vivo by resident alveolar macrophages.  J Exp Med. 1993;  177 397-407
  • 57 Ferro T J, Monos D S, Spear B T. Carbohydrate differences in HLA-DR molecules synthesized by alveolar macrophages and blood monocytes.  Am Rev Respir Dis. 1987;  135 1340-1344
  • 58 Rich E A, Tweardy D J, Fujiwara H, Ellner J J. Spectrum of immunoregulatory functions and properties of human alveolar macrophages.  Am Rev Respir Dis. 1987;  136 258-265
  • 59 Denham S, Rowland I J. Inhibition of the reactive proliferation of lymphocytes by activated mcrophages: the role of nitric oxide.  Clin Exp Immunol. 1992;  87 157-162
  • 60 Thomassen M J, Buhrow L T, Connors M J, Kaneko T, Erzurum S C, Kavuru M S. Nitric oxide inhibits inflammatory cytokine production by human alveolar macrophages.  Am J Respir Cell Mol Biol. 1997;  17 279-283
  • 61 Bingisser R M, Tilbrook P A, Holt P G, Kees U R. Macrophage-derived nitric oxide regulates T cell activation via reversible disruption of the Jak3/STAT5 signaling pathway.  J Immunol. 1998;  160 5729-5734
  • 62 Yarbrough Jr W C, Wilkes D S, Weissler J C. Human alveolar macrophages inhibit receptor-mediated increases in intracellular calcium concentration in lymphocytes.  Am J Respir Cell Mol Biol. 1991;  5 411-415
  • 63 Chelen C J, Yu F, Feeman G J et al.. Human alveolar macrophages present antigen ineffectively due to defective expression of B7 costimulatory cell surface molecules.  J Clin Invest. 1995;  95 1415-1421
  • 64 Strickland D, Kees U R, Holt P G. Regulation of T-cell activation in the lung: alveolar macrophages induce reversible T-cell anergy in vitro associated with inhibition of interleukin-2 receptor signal transduction.  Immunology. 1996;  87 250-258
  • 65 Saltini C, Kirby M, Trapnell B C, Tamura N, Crystal R G. Biased accumulation of T lymphocytes with “memory”-type CD45 leukocyte common antigen gene expression on the epithelial surface of the human lung.  J Exp Med. 1990;  171 1123-1140
  • 66 Balaji K N, Schwander S K, Rich E A, Boom W H. Alveolar macrophages as accessory cells for human γδ T cells activated by Mycobacterium tuberculosis .  J Immunol. 1995;  154 5959-5968
  • 67 Vecchiarelli A, Dottorini M, Pietrella D et al.. Role of human alveolar macrophages as antigen-presenting cells in Cryptococcus neoformans infection.  Am J Respir Cell Mol Biol. 1994;  11 130-137
  • 68 Holt P G. Antigen presentation in the lung.  Am J Respir Crit Care Med. 2000;  162 S151-S156
  • 69 Banchereau J, Briere F, Caux C et al.. Immunobiology of dendritic cells.  Annu Rev Immunol. 2000;  18 767-811
  • 70 Zissel G, Ernst M, Schlaak M. Muller-Quernheim: accessory function of alveolar macrophages from patients with sarcoidosis and other granulomatous and nongranulomatous lung diseases.  J Investig Med. 1997;  45 75-86
  • 71 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. 1997;  17 91-96
  • 72 Somoskovi A, Zissel G, Ziegenhagen M W, Schlaak M, Muller-Quernheim J. Accessory function and costimulatory molecule expression of alveolar macrophages in patients with tuberculosis.  Immunobiology. 2000;  201 450-460
  • 73 Twigg H L, Iwamoto G K, Soliman D M. Role of cytokines in alveolar macrophage accessory cell function in HIV-infected individuals.  J Immunol. 1992;  149 1462-1469
  • 74 Agostini C, Facco M, Chilosi M, Semenzato G. Alveolar macrophage-T cell interactions during Th1-type sarcoid inflammation.  Microsc Res Tech. 2001;  53 278-287
  • 75 Bilyk N, Holt P G. Inhibition of the immunosuppressive activity of resident pulmonary alveolar macrophages by granulocyte/macrophage colony-stimulating factor.  J Exp Med. 1993;  177 1773-1777
  • 76 Weissler J C, Mendelson C, Moya F, Yarbrough Jr W C. Effect of insterstitial lung disease macrophages on T-cell signal transduction.  Am J Respir Crit Care Med. 1994;  149 191-196
  • 77 Tang C, Inman M D, van Rooijen N et al.. Th type 1-stimulating activity of lung macrophages inhibits Th2-mediated allergic airway inflammation by an IFN-γ-dependent mechanism.  J Immunol. 2001;  166 1471-1481
  • 78 Tang C, Ward C, Reid D, Bish R, O'Byrne P M, Walters E H. Normally suppressing CD40 coregulatory signals delivered by airway macrophages to Th2 lymphocytes are defective in patients with atopic asthma.  J Allergy Clin Immunol. 2001;  107 863-870
  • 79 Wilkes D S, Yarbrough W C, Weissler J C. Human alveolar macrophages inhibit immunoglobulin production in response to direct B cell mitogen.  Am J Respir Cell Mol Biol. 1993;  9 141-147
  • 80 Bauer W, Gorny N K, Baumann H R, Morell A. T-lymphocyte subsets and immunoglobulin concentrations in bronchoalveolar lavage of patients with sarcoidosis and high and low intensity alveolitis.  Am Rev Respir Dis. 1985;  132 1060-1065
  • 81 Wilkes D S, Weissler J C. Alloantigen-induced immunoglobulin production in human lung: differential effects of accessory cell populations on IgG synthesis.  Am J Respir Cell Mol Biol. 1994;  10 339-346
  • 82 MacLean J A, Xia W, Pinto C E, Zhao L, Liu H-W, Kradin R L. Sequestration of inhaled particulate antigens by lung phagocytes: a mechanism for the effective inhibition of pulmonary cell-mediated immunity.  Am J Pathol. 1996;  148 657-666
  • 83 Wijburg O LC, DiNatale S, Vadolas J, van Rooijen N, Strugnell R A. Alveolar macrophage regulate the induction of primary cytoxic T-lymphocyte responses during influenza virus infection.  J Virol. 1997;  71 9450-9457
  • 84 Debrick J E, Campbell P A, Staerz U D. Macrophages as accessory cells for class I MHC-restricted immune responses.  J Immunol. 1991;  147 2846-2851
  • 85 Quentmeier H, Klaucke J, Muhlradt F P, Drexler H G. Role of IL-6, IL-2, and IL-4 in the in vitro induction of cytotoxic T cells.  J Immunol. 1992;  149 3316-3320
  • 86 Plata F, Autran B, Martins L P et al.. AIDS virus-specific cytotoxic T lymphocytes in lung disorders.  Nature. 1987;  328 348-351
  • 87 Lee W C, McConnell I, Blacklaws B A. Cytotoxic activity against Maedi-visna virus-infected macrophages.  J Virol. 1994;  68 8331-8338
  • 88 Bingisser R, Stey C, Weller M, Groscurth P, Russi E, Frei K. Apoptosis in human alveolar macrophages is induced by endotoxin and is modulated by cytokines.  Am J Respir Cell Mol Biol. 1996;  15 64-70

Homer L Twigg IIIM.D. 

Indiana University Medical Center

1481 West 10th St., 111P-IU

Indianapolis, IN 46202

Email: htwig@iupui.edu

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