Phagocytosis: Enhancement

Leanne Peiser, Amgen, Seattle, USA
Siamon Gordon, Oxford University, Oxford, UK

Published online: December 2009

DOI: 10.1002/9780470015902.a0001214.pub2

Phagocytosis is the process of engulfment of particles by phagocytic cells, such as macrophages and neutrophils. The ingestion of pathogens, tissue debris or apoptotic cells by these cells may be enhanced by coating the particle with host molecules called opsonins, which allow the recognition and subsequent ingestion of the particles by phagocytic receptors. There are numerous opsonins, including complement-derived proteins such as iC3b and immunoglobulin G, which are recognized by specialized receptors including complement receptor type 3 and FcR. The failure of efficient uptake of particles and apoptotic cell debris can have deleterious effects on the host such as leading to the spread of infection and the generation of autoimmune conditions, such as systemic lupus erythematosus.

Key concepts:

  • Efficient removal of particulate matter by phagocytic cells requires direct recognition of the particle by the cell along with indirect binding via host-derived molecules known as opsonins.
  • Enhanced phagocytic uptake of pathogens and dying cells is mediated by a number of overlapping opsonins and phagocytic receptors.
  • Ingested particles are recognized by a number of different receptors which may cooperate with each other to modulate their function/activity.
  • Though multiple receptors can mediate phagocytosis, there are subtle differences in their signalling and cell biology that can result in different cellular outcomes downstream of uptake.
  • Defects in the removal of both pathogens and apoptotic cells can lead to increased susceptibility to infection and autoimmune diseases.

Keywords: opsonin; complement; antibody receptors; macrophages; neutrophils; phagocytosis

Figure 1. Opsonins and their receptors. A broad range of opsonins exist to detect invading pathogens and apoptotic cells. Note the number of overlapping opsonins and receptors for detection of either dying cells or bacteria. Refer to the text for details on what molecules and structures on the pathogens or apoptotic cells are recognized by the various opsonins. These structures range from general sugar residues in the case of MBL to phosphotidyl serine on apoptotic cells to specific antigens detected by antibodies.
Figure 2. FcRs and CR3 ingest particles through different mechanisms. Stage 1: initial contact. The opsonin-coated particle, IgG (a) or iC3b (b), binds the surface of the phagocyte through FcR (a) or CR3 (b). The initial receptor–ligand interaction recruits more receptors to the area. Stage 2: pseudopod extension. At the point of contact, pseudopodia extend around the particle, forming contacts where the receptors bind ligand. (a) In FcR-mediated phagocytosis the pseudopodia appear to envelop the particle by projections from the cell surface. The sequential binding of receptors to ligands is thought to draw the pseudopodia along with it. On the intracellular surface, actin and actin-associated molecules like vinculin, paxillin and tyrosine kinases surround the particle. (b) CR3-mediated phagocytosis is not associated with large pseudopodia, instead the particle appears to sink into the cell. Actin and associated molecules are found in foci on the intracellular surface beneath the particle. The membrane is not as tightly apposed to the particle as with FcR. Small GTPases, Cdc 42 and Rac (a) or Rho (b), associate with the actin and are involved with actin reorganization. Stage 3: internalization. The pseudopodia surround the particle and fuse. (a) Internalization of the particle, but not pseudopod extension, requires the activation of signalling molecules, like Syk tyrosine kinases, phospholipase C and protein kinase C (PKC) and the actin cytoskeleton. (b) Uptake via CR3 does not depend on activation of Syk tyrosine kinases, but on the actin cytoskeleton, microtubules and signalling molecules like PKC. Stage 4: phagosome processing. After fusion of the pseudopodia, the actin surrounding the particles is shed rapidly; the resulting phagosome is drawn into the cell and fuses with the endocytic pathway. This leads to maturation of the phagosome, characterized by acidification of the phagosome, acquisition of proteolytic enzymes and generation of superoxide radicals (only). Ultimately, the particle may be degraded. Note: Both FcR and CR3 are heterogeneous and little attention has been paid hitherto in defining the possible different roles of each receptor species.
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 References
    Allen LH and Aderem A (1996) Molecular definition of distinct cytoskeletal structures involved in complement and Fc receptor-mediated phagocytosis in macrophages. Journal of Experimental Medicine 184: 627–637.
    Baorto DM, Gao Z, Malaviya R et al. (1997) Survival of Fim H-expressing enterobacteria in macrophages relies on glycolipid traffic. Nature 389: 636–639.
    Blander JM and Medzhitov R (2004) Regulation of phagosome maturation by signals from toll-like receptors. Science 304: 1014–1018.
    Braun A, Gessner JE, Varga-Szabo D et al. (2009) STIM1 is essential for Fc gamma receptor activation and autoimmune inflammation. Blood 113(5): 1097–1104.
    Caron E and Hall A (1998) Identification of two distinct mechanisms of phagocytosis controlled by different Rho GTPases. Science 282: 1717–1721.
    Cox D and Greenberg S (2001) Phagocytic signaling strategies: Fc(gamma) receptor-mediated phagocytosis as a model system. Seminars in Immunology 13: 339–345.
    Cox D, Tseng CC, Bjekic G and Greenberg S (1999) A requirement for phosphatidylinositol 3-kinase in pseudopod extension. Journal of Biological Chemistry 274(3): 1240–1247.
    Gagnon E, Duclos S, Rondeau C et al. (2002) Endoplasmic reticulum-mediated phagocytosis is a mechanism of entry into macrophages. Cell 110: 119–131.
    Gorgani NN, He JQ, Katschke KJ Jr et al. (2008) Complement receptor of the Ig superfamily enhances complement-mediated phagocytosis in a subpopulation of tissue resident macrophages. Journal of Immunology 181: 7902–7908.
    Griffin FM Jr, Griffin JA, Leider JE and Silverstein SC (1975) Studies on the mechanism of phagocytosis I. Requirements for the circumferential attachment of particle-bound ligands to specific receptors on the macrophage plasma membrane. Journal of Experimental Medicine 142: 1263–1282.
    Griffin FM Jr, Griffin JA and Silverstein SC (1976) Studies on the mechanism of phagocytosis II. The interaction of macrophages with anti-immunoglobulin IgG-coated bone marrow-derived lymphocytes. Journal of Experimental Medicine 144: 788–809.
    Hanayama R, Tanaka M, Miyasaka K et al. (2004) Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8–deficient mice. Science 304: 1147–1150.
    Helmy KY, Katschke KJ Jr, Gorgani NN et al. (2006) CRIg: a macrophage complement receptor required for phagocytosis of circulating pathogens. Cell 124: 915–927.
    Honoré C, Hummelshoj T, Hansen BE et al. (2007) The innate immune component ficolin 3 (Hakata antigen) mediates the clearance of late apoptotic cells. Arthritis and Rheumatism 56: 1598–1607.
    Huynh KK, Kay JG, Stow JL and Grinstein S (2007) Fusion, fission, and secretion during phagocytosis. Physiology 22: 366–372.
    Jensen ML, Honoré C, Hummelshøj T et al. (2007) Ficolin-2 recognizes DNA and participates in the clearance of dying host cells. Molecular Immunology 44: 856–865.
    van Lookeren Campagne M, Wiesmann C and Brown EJ (2007) Macrophage complement receptors and pathogen clearance. Cellular Microbiology 9(9): 2095–2102.
    Lowry MB, Duchemin A-M, Robinson JM and Anderson CL (1998) Functional separation of pseudopod extension and particle internalisation during Fc receptor-mediated phagocytosis. Journal of Experimental Medicine 187: 161–176.
    Mantovani A, Garlanda C, Doni A and Bottazzi B (2008) Pentraxins in innate immunity: from C-reactive protein to the long pentraxin PTX3. Journal of Clinical Immunology 28: 1–13.
    book Metchnikoff E (1893) Lectures on the Comparative Pathology of Inflammation. Reprinted in 1968. New York: Dover Publications.
    Miyanishi M, Tada K, Koike M et al. (2007) Identification of Tim4 as a phosphatidylserine receptor. Nature 450: 435–439.
    Nepomuceno RR and Tenner AJ (1998) C1qRp, the C1q receptor that enhances phagocytosis, is detected specifically in human cells of myeloid lineage, endothelial cells and platelets. Journal of Immunology 160: 1929–1935.
    Nimmerjahn F and Ravetch JV (2007) Fc-receptors as regulators of immunity. Advances in Immunology 96: 179.
    Park D, Tosello-Trampont AC, Elliott MR et al. (2007) BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module. Nature 450: 430–434.
    Peiser L, De Winther MP, Makepeace K et al. (2002) The class A macrophage scavenger receptor is a major pattern recognition receptor for Neisseria meningitidis which is independent of lipopolysaccharide and not required for secretory responses. Infection and Immunity 70(10): 5346–5354.
    Radaev S and Sun PD (2001) Recognition of IgG by Fc gamma receptor. The role of Fc glycosylation and the binding of peptide inhibitors. Journal of Biological Chemistry 276(19): 16469–16477.
    Rock KL and Shen L (2005) Cross-presentation: underlying mechanisms and role in immune surveillance. Immunological Reviews 207: 166–183.
    Runza VL, Schwaeble W and Mannel DN (2008) Ficolins: novel pattern recognition molecules of the innate immune response. Immunobiology 213: 297–306.
    Touret N, Paroutis P, Terebiznik M et al. (2005) Quantitative and dynamic assessment of the contribution of the ER to phagosome formation. Cell 123: 157–170.
    Wright SD and Silverstein SC (1983) Receptors for C3b and C3bi promote phagocytosis but not the release of toxic oxygen from human phagocytes. Journal of Experimental Medicine 158: 2016–2023.
    Yates RM and Russell DG (2005) Phagosome maturation proceeds independently of stimulation of toll-like receptors 2 and 4. Immunity 23: 409–417.
    Zhang J, Guo J, Dzhagalov I and He YW (2005) An essential function for the calcium-promoted Ras inactivator in Fcgamma receptor-mediated phagocytosis. Nature Immunology 6: 911–919.
 Further Reading
    Blystone SD, Graham IL, Lindberg FP and Brown EJ (1994) Integrin v 3 differentially regulates adhesive and phagocytic functions of the fibronectin receptors 5 1. Journal of Cell Biology 127: 1129–1137.
    book Gordon S (1995) "Mononuclear phagocyte system and tissue homeostasis". In: Weatherall DJ, Ledingham JG and Warrell DA (eds) Oxford Textbook of Medicine, pp. 84–95. Oxford: Oxford University Press.
    book Gordon S (ed.) (1999) Phagocytes and Pathogens. Greenwich, CT: JAI Press.
    book Greenberg S and Silverstein SC (1993) "Phagocytosis". In: Paul WE (ed.) Fundamental Immunology, 3rd edn, pp. 941–964. New York: Raven Press Ltd.
    Jutras I and Desjardin M (2005) Phagocytosis: at the crossroads of innate and adaptive immunity. Annual Review of Cell and Developmental Biology 21: 511–527.
    book Law SKA and Reid KBM (1995) Complement, 2nd edn. Oxford: IRL Press.
    Lu J (1997) Collectins: collectors of the microorganisms for the innate immune system. BioEssays 19: 509–518.
    Nimmerjahn F and Ravetch JV (2007) Fc-receptors as regulators of immunity. Advances in Immunology 96: 179–204.
    Peiser L and Gordon S (1995) Phagocytosis. Trends in Cell Biology 5(3): 85–142. [special edition of this journal].
    Stuart LM and Ezekowitz RAB (2005) Phagocytosis: elegant complexity. Immunity 22: 539–550.
    Swanson JA (2008) Shaping cups into phagosomes and macropinosomes. Nature Reviews. Molecular Cell Biology 9(8): 639–649.
    Touret N, Paroutis P and Grinstein S (2005) The nature of the phagosomal membrane: endoplasmic reticulum versus plasmalemma. Journal of Leukocyte Biology 77(6): 878–885.

Related Sub-Topics:

Innate Immunity | Cells of the Immune System | Intracellular and Extracellular Signalling
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Article Title: Phagocytosis: Enhancement
 
How to Cite close
Peiser, Leanne, and Gordon, Siamon(Dec 2009) Phagocytosis: Enhancement. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001214.pub2]