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Molecular Mechanisms of Phagosome Formation

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  • Authors: Valentin Jaumouillé1, Sergio Grinstein2
  • Editor: Siamon Gordon3
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada; 2: Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada; 3: Oxford University, Oxford, United Kingdom
    • Source: microbiolspec May 2016 vol. 4 no. 3 doi:10.1128/microbiolspec.MCHD-0013-2015
  • Received 05 June 2015 Accepted 17 July 2015 Published 06 May 2016
  • Sergio Grinstein, [email protected]
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  • Abstract:

    Phagocytosis refers to the active process that allows cells to take up large particulate material upon binding to surface receptors. The discovery of phagocytosis in 1883 by Elie Metchnikoff, leading to the concept that specialized cells are implicated in the defense against microbes, was one of the starting points of the field of immunology. After more than a century of research, phagocytosis is now appreciated to be a widely used process that enables the cellular uptake of a remarkable variety of particles, including bacteria, fungi, parasites, viruses, dead cells, and assorted debris and solid materials. Uptake of foreign particles is performed almost exclusively by specialized myeloid cells, commonly termed “professional phagocytes”: neutrophils, monocytes, macrophages, and dendritic cells. Phagocytosis of microbes not only stops or at least restricts the spread of infection but also plays an important role in regulating the innate and adaptive immune responses. Activation of the myeloid cells upon phagocytosis leads to the secretion of cytokines and chemokines that convey signals to a variety of immune cells. Moreover, foreign antigens generated by the degradation of microbes following phagocytosis are loaded onto the major histocompatibility complex for presentation to specific T lymphocytes. However, phagocytosis is not restricted to professional myeloid phagocytes; an expanding diversity of cell types appear capable of engulfing apoptotic bodies and debris, playing a critical role in tissue remodeling and in the clearance of billions of effete cells every day.

  • Citation: Jaumouillé V, Grinstein S. 2016. Molecular Mechanisms of Phagosome Formation. Microbiol Spectrum 4(3):MCHD-0013-2015. doi:10.1128/microbiolspec.MCHD-0013-2015.

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2016-05-06
2020-08-06

Abstract:

Phagocytosis refers to the active process that allows cells to take up large particulate material upon binding to surface receptors. The discovery of phagocytosis in 1883 by Elie Metchnikoff, leading to the concept that specialized cells are implicated in the defense against microbes, was one of the starting points of the field of immunology. After more than a century of research, phagocytosis is now appreciated to be a widely used process that enables the cellular uptake of a remarkable variety of particles, including bacteria, fungi, parasites, viruses, dead cells, and assorted debris and solid materials. Uptake of foreign particles is performed almost exclusively by specialized myeloid cells, commonly termed “professional phagocytes”: neutrophils, monocytes, macrophages, and dendritic cells. Phagocytosis of microbes not only stops or at least restricts the spread of infection but also plays an important role in regulating the innate and adaptive immune responses. Activation of the myeloid cells upon phagocytosis leads to the secretion of cytokines and chemokines that convey signals to a variety of immune cells. Moreover, foreign antigens generated by the degradation of microbes following phagocytosis are loaded onto the major histocompatibility complex for presentation to specific T lymphocytes. However, phagocytosis is not restricted to professional myeloid phagocytes; an expanding diversity of cell types appear capable of engulfing apoptotic bodies and debris, playing a critical role in tissue remodeling and in the clearance of billions of effete cells every day.

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Molecular Mechanisms of Phagosome Formation
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Citation: Jaumouillé V, Grinstein S. 2016. Molecular mechanisms of phagosome formation. microbiolspec 4(3): doi:10.1128/microbiolspec.MCHD-0013-2015
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FIGURE 1

Temporal sequence of particle uptake by phagocytosis. Particle surface molecules are engaged by phagocyte receptors. Actin-driven membrane dynamics facilitate the detection of surrounding particles. Engagement and activation of the receptor lead to the induction of signaling cascades that elicit actin reorganization. Actin polymerization progresses around the particle, accompanied by further engagement of receptors. Actin clearance and focal exocytosis at the base of the cup facilitate particle engulfment. Once the particle is fully surrounded, membrane fusion at the rims of the cup seals the phagosome and separates it from the plasma membrane.

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FIGURE 1

Temporal sequence of particle uptake by phagocytosis. Particle surface molecules are engaged by phagocyte receptors. Actin-driven membrane dynamics facilitate the detection of surrounding particles. Engagement and activation of the receptor lead to the induction of signaling cascades that elicit actin reorganization. Actin polymerization progresses around the particle, accompanied by further engagement of receptors. Actin clearance and focal exocytosis at the base of the cup facilitate particle engulfment. Once the particle is fully surrounded, membrane fusion at the rims of the cup seals the phagosome and separates it from the plasma membrane.

Source: microbiolspec May 2016 vol. 4 no. 3 doi:10.1128/microbiolspec.MCHD-0013-2015
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FIGURE 2

Signaling cascades leading to actin reorganization during FcγR-mediated phagocytosis. Engagement and aggregation of FcγRs activate tyrosine kinases (yellow), which recruit multiple adaptor proteins (green). The FcγR signaling complex activates lipid modification enzymes (orange), GEFs (pink), actin modulators (navy blue), and Rho GTPases (purple). By activating nucleation-promoting factors (brown), they stimulate the activity of the Arp2/3 complex (red), which nucleates actin polymerization into a branched network. Abbreviations: PIP, phosphatidylinositol 3,4,5-trisphosphate; PLD, phospholipase D.

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FIGURE 2

Signaling cascades leading to actin reorganization during FcγR-mediated phagocytosis. Engagement and aggregation of FcγRs activate tyrosine kinases (yellow), which recruit multiple adaptor proteins (green). The FcγR signaling complex activates lipid modification enzymes (orange), GEFs (pink), actin modulators (navy blue), and Rho GTPases (purple). By activating nucleation-promoting factors (brown), they stimulate the activity of the Arp2/3 complex (red), which nucleates actin polymerization into a branched network. Abbreviations: PIP, phosphatidylinositol 3,4,5-trisphosphate; PLD, phospholipase D.

Source: microbiolspec May 2016 vol. 4 no. 3 doi:10.1128/microbiolspec.MCHD-0013-2015
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FIGURE 3

Molecular mechanism of fungi phagocytosis by Dectin-1. Engagement of Dectin-1 leads to the phosphorylation of its hemi-ITAM by SFKs and the recruitment of Syk. Activation of these kinases is facilitated by the exclusion of the tyrosine phosphatases CD45 and CD148 from the phagocytic cup. The combined action of SFKs, Syk, PI3K, and PKC lead to the activation of the small GTPases Rac and Cdc42, which activate Arp2/3-driven actin polymerization.

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FIGURE 3

Molecular mechanism of fungi phagocytosis by Dectin-1. Engagement of Dectin-1 leads to the phosphorylation of its hemi-ITAM by SFKs and the recruitment of Syk. Activation of these kinases is facilitated by the exclusion of the tyrosine phosphatases CD45 and CD148 from the phagocytic cup. The combined action of SFKs, Syk, PI3K, and PKC lead to the activation of the small GTPases Rac and Cdc42, which activate Arp2/3-driven actin polymerization.

Source: microbiolspec May 2016 vol. 4 no. 3 doi:10.1128/microbiolspec.MCHD-0013-2015
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FIGURE 4

Actin reorganization during complement-mediated phagocytosis by the integrin αβ (CR3). Rap-1-mediated inside-out activation of CR3 via its association with talin can be induced by various receptors, including TLRs, G protein-coupled receptors (GPCRs), and Fc receptors. Engagement of CR3 leads to the activation of PI3K and the small GTPases RhoA and RhoG. RhoA activates the actin nucleator of the formin family mDia1, which stimulates actin polymerization into a linear network, whereas the serine/threonine kinase ROCK activates myosin II, which favors the recruitment of the Arp2/3 complex, leading to the polymerization of a branched actin network.

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FIGURE 4

Actin reorganization during complement-mediated phagocytosis by the integrin αβ (CR3). Rap-1-mediated inside-out activation of CR3 via its association with talin can be induced by various receptors, including TLRs, G protein-coupled receptors (GPCRs), and Fc receptors. Engagement of CR3 leads to the activation of PI3K and the small GTPases RhoA and RhoG. RhoA activates the actin nucleator of the formin family mDia1, which stimulates actin polymerization into a linear network, whereas the serine/threonine kinase ROCK activates myosin II, which favors the recruitment of the Arp2/3 complex, leading to the polymerization of a branched actin network.

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FIGURE 5

Signaling events in phagocytosis of apoptotic bodies mediated by TIM-4. TIM-4 and integrins cooperate to take up apoptotic bodies. SFK, FAK, and PI3K activities lead to the stimulation of Vav3, a GEF for RhoA and Rac, which activate the actin nucleators mDia and Arp2/3, respectively. oxPS; oxidized phosphatidylserine.

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FIGURE 5

Signaling events in phagocytosis of apoptotic bodies mediated by TIM-4. TIM-4 and integrins cooperate to take up apoptotic bodies. SFK, FAK, and PI3K activities lead to the stimulation of Vav3, a GEF for RhoA and Rac, which activate the actin nucleators mDia and Arp2/3, respectively. oxPS; oxidized phosphatidylserine.

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Tables

Molecular Mechanisms of Phagosome Formation
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Citation: Jaumouillé V, Grinstein S. 2016. Molecular mechanisms of phagosome formation. microbiolspec 4(3): doi:10.1128/microbiolspec.MCHD-0013-2015
/content/microbiolspec/10.1128/microbiolspec.MCHD-0013-2015.T1
TABLE 1

Phagocytic receptors and their specific ligands

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TABLE 1

Phagocytic receptors and their specific ligands

Source: microbiolspec May 2016 vol. 4 no. 3 doi:10.1128/microbiolspec.MCHD-0013-2015

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