Phagocytosis: Enhancement

Abstract

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