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  • Review Article
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Information processing during phagocytosis

Key Points

  • In addition to mediating the killing of microorganisms and the clearance of debris, the process of phagocytosis itself is an integral part of how macrophages and dendritic cells acquire information about a threat and elicit inflammatory responses that are appropriate to that threat.

  • Interactions of target particles with the cell surface can yield information about particle size, shape and composition. This information is interpreted by immune cells and incorporated into decisions such as whether to internalize the targets and what type of pro-inflammatory cytokines and chemokines to produce.

  • The process of forming a phagosome and pinching it off from the plasma membrane can influence the duration of signalling from membrane receptors, the concentration of such receptors into the newly formed phagosomes, and the way in which signalling molecules inside the cell interact with those receptors.

  • Signalling from within a phagosome can influence the processing and presentation of antigens derived specifically from the cargo in that phagosome.

  • The degradation of microorganisms within phagosomes releases cryptic ligands, which can subsequently be detected by receptors such as Toll-like receptor 2 (TLR2) and TLR9 to further regulate inflammatory responses.

  • Inflammasomes — which are caspase 1-containing protein complexes that regulate the release of interleukin-1β (IL-1β) and IL-18 — have been shown to be regulated by phagocytosis in various settings.

Abstract

Phagocytosis — the process by which macrophages, dendritic cells and other myeloid phagocytes internalize diverse particulate targets — is a key mechanism of innate immunity. The molecular and cellular events that underlie the binding of targets to a phagocyte and their engulfment into phagosomes have been extensively studied. More recent data suggest that the process of phagocytosis itself provides information to myeloid phagocytes about the nature of the targets they are engulfing and that this helps to tailor inflammatory responses. In this Review, we discuss how such information is acquired during phagocytosis and how it is processed to coordinate an immune response.

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Figure 1: Information processing at different stages of phagocytosis.
Figure 2: Phagocytic synapse formation permits dectin 1 to distinguish between soluble and particulate β-glucans.
Figure 3: TLR4 signal transduction from the cell surface, endosomes and phagosomes.
Figure 4: Macrophages can differentiate between live and dead E. coli through the detection of 'vita-PAMPs'.

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Glossary

Toll-like receptors

(TLRs). A type of pattern-recognition receptor that recognizes unique structures that are associated with infection or tissue damage. Signalling through TLRs promotes inflammatory immune responses, cytokine production and cell activation.

Phagocyte NADPH oxidase

An enzyme system that consists of multiple cytosolic and membrane-bound subunits. The complex is assembled in activated myeloid cells, mainly on the phagolysosomal membrane. NADPH oxidase uses electrons from NADPH to reduce molecular oxygen to form superoxide anions. Superoxide anions are enzymatically converted to hydrogen peroxide, which is converted by myeloperoxidase to hypochlorous acid, a highly toxic and microbicidal agent.

Pseudopodia

Transient cell membrane protrusions that extend around a target particle to engulf it. Pseudopodia also occur during cell migration.

Frustrated phagocytosis

Occurs when a phagocyte is unable to engulf its target because the target is physically too large to encompass. This can lead to the release of potentially toxic pro-inflammatory mediators into the surrounding environment.

Immunological synapse

A stable region of contact between a T cell and an antigen-presenting cell that forms through the interaction of adhesion molecules on the surface of both cells. The mature immunological synapse contains two distinct stable membrane domains: a central cluster of T cell receptors known as the central supramolecular activation cluster (cSMAC) and a surrounding ring of adhesion molecules known as the peripheral supramolecular activation cluster (pSMAC).

Mechanotransducer

A system for converting mechanical energy into chemical signals.

Pathogen-associated molecular patterns

(PAMPs). Molecular patterns that are found in microorganisms but not in mammalian cells. Examples include terminally mannosylated and polymannosylated compounds (which bind to the mannose receptor) and various microbial components, such as bacterial lipopolysaccharide, hypomethylated DNA, flagellin and double-stranded RNA (all of which bind to Toll-like receptors).

Inflammasome

A large multiprotein complex that contains certain NOD-like receptors, RIG-I-like receptors and HIN200 proteins, together with the adaptor protein ASC and pro-caspase 1. Assembly of the inflammasome leads to the activation of caspase 1, which cleaves pro-interleukin-1β (pro-IL-1β) and pro-IL-18 to generate the active forms of these pro-inflammatory cytokines.

Pyroptosis

An inflammatory form of cell death that is associated with antimicrobial responses and is dependent on inflammasome activation.

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Underhill, D., Goodridge, H. Information processing during phagocytosis. Nat Rev Immunol 12, 492–502 (2012). https://doi.org/10.1038/nri3244

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