Phagocytosis: Enhancement


Phagocytosis is the process of cellular engulfment of particles. Professional phagocytes, such as macrophages, neutrophils and dendritic cells, are the most efficient at mediating particle ingestion though nonprofessional phagocytes, such as fibroblasts and epithelial cells, can ingest neighbouring dying cells. Pathogen ingestion for killing and antigen processing for presentation are important components of innate and acquired immunity, and removal of dying cells is critical for tissue homeostasis. The uptake of pathogens, tissue debris or apoptotic 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 recognised by specialised receptors including complement receptor type 3 and FcγR. 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 (SLE). CR3 and FcγR are the most studied of the opsonic phagocytic receptors.

Key Concepts

  • Phagocytic receptors can recognise their particle by either direct binding or indirectly after it is coated with host molecules called opsonins.
  • Professional phagocytic cells, such as dendritic cells, monocytes and macrophages, express numerous receptors capable of mediating particle ingestion.
  • Enhanced phagocytic uptake of pathogens and dying cells is mediated by a number of overlapping opsonins and phagocytic receptors.
  • Ingested particles are recognised 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.
  • Removal of apoptotic cells by professional phagocytes typically results in the release of antiinflammatory mediators, while phagocytosis of pathogens can cause inflammation.
  • 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; apoptotic cell; antibodies; collectins; ficolins

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 recognised by the various opsonins. These structures range from general sugar residues in the case of MBL to phosphatidyl 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 such as 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 reorganisation. Stage 3: internalisation. The pseudopodia surround the particle and fuse. (a) Internalisation of the particle, but not pseudopod extension, requires the activation of signalling molecules, such as 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 such as 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, characterised 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.


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.

Bohdanowicz M, Cosio G, Backer JM and Grinstein S (2010) Class I and Class III phosphoinositide 3‐kinases are required for actin polymerization that propels phagosomes. Journal of Cell Biology 191: 999–1012. DOI: 10.1083/jcb.201004005.

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.

Flannagan RS, Canton J, Furuya W, Glogauer M and Grinstein S (2014) The phophatidylserine receptor TIM4 utilizes integrins as coreceptors to effect phagocytosis. Molecular Biology of the Cell 25: 1511–1522. DOI: 10.1091/mbc.E13-04-0212.

Gagnon E, Duclos S, Rondeau C, et al. (2002) Endoplasmic reticulum‐mediated phagocytosis is a mechanism of entry into macrophages. Cell 110: 119–131.

Gadjeva M, Verschoor A, Brockman MA, et al. (2002) Macrophage‐derived complement component C4 can restore humoral immunity in C4‐deficient mice. Journal of Immunology 169: 5489–5495.

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.

Hall AB, Gakidis MA, Glogauer M, et al. (2006) Requirements for VAV guanine nucleotide exchange factors and Rho GTPases in FcgammaR‐ and complement‐mediated phagocytosis. Immunity 24: 305–316.

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.

Holowka D, Sil D, Torigoe C and Baird B (2007) Insights into immunoglobulin E receptor signaling from structurally defined ligands. Immunological Reviews 217: 269–279.

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.

Jarva H, Jokiranta TS, Wurzner R and Meri S (2003) Complement resistance mechanisms of streptococci. Molecular Immunology 40: 95–107.

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.

Jung K, Kang M, Park C, et al. (2012) Protective role of V‐set and immunoglobulin domain‐containing 4 expressed on kupffer cells during immune‐mediated liver injury by inducing tolerance of liver T‐ and natural killer T‐cells. Hepatology 56: 1838–1848. DOI: 10.1002/hep.25906.

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 γ 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.

Mazaheri F, Breus O, Durdu S, et al. (2014) Distinct roles for BAI1 and TIM‐4 in the engulfment of dying neurons by microglia. Nature Communications 5: 4046. DOI: 10.1038/ncomms5046.

Mazzolini J, Herit F, Bouchet J, et al. (2010) Inhibition of phagocytosis in HIV‐1‐infected macrophages relies on Nef‐dependent alteration of focal delivery of recycling compartments. Blood 2115: 4226–4236. DOI: 10.1182/blood-2009-12-259473.

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.

Niedergang F, Colucci‐Guyon E, Dubois T, Raposo G and Chavrier P (2003) ADP ribosylation factor 6 is activated and controls membrane delivery during phagocytosis in macrophages. Journal of Cell Biology 16: 1143–1150.

Nimmerjahn F and Ravetch JV (2007) Fc‐receptors as regulators of immunity. Advances in Immunology 96: 179.

Nishi C, Toda S, Segawa K and Nagata S (2014) Tim4‐ and MerTK‐mediated engulfmentof apoptotic cells by peritoneal macrophages. Molecular Cell. Biology 34: 1512–1520.

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.

Patel PC and Harrison RE (2008) Membrane ruffles capture C3bi‐opsonized particles in activated macrophages. Molecular Biology of the Cell 19: 4628–4639. DOI: 10.1091/mbc.E08-02-0223.

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.

Schwartz JT, Barker JH, Long ME, et al. (2012) Natural IgM mediated complement‐dependent uptake of Francisella tularensis by human neutrophils via complement receptors 1 and 3 in nonimmune serum. Journal of Immunology 189: 3064–3077.

Scott CC, Dobson W, Betelho RJ, et al. (2005) Phosphatidylinositol‐4‐5bisphosphate hydrolysis directs actin remodeling during phagocytosis. Journal of Cell Biology 11: 139–149.

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

Bottazzi B, Doni A, Garlanda C and Mantovani A (2010) An integrated view of humoral innate immunity: pentraxins as a paradigm. Annual Review of Immunology 28: 157–183.

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.

Gordon S (ed.) (1999) Phagocytes and Pathogens. Greenwich, CT: JAI Press.

Greenberg S and Silverstein SC (1993) Phagocytosis. In: Paul WE (ed.) Fundamental Immunology, 3rd edn, pp. 941–964. New York: Raven Press Ltd.

Holers VM (2014) Complement and its receptors: new insights into human disease. Annual Review of Immunology 32: 433–459. DOI: 10.1146/annurev-immunol-032713-120154.

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.

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.

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Peiser, Leanne(Jun 2016) Phagocytosis: Enhancement. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0001214.pub3]