Phagosome Formation

The process of engulfing a foreign particle - phagocytosis - is of fundamental importance for a wide diversity of organisms. From simple unicellular organisms that use phagocytosis to obtain their next meal, to complex metazoans in which phagocytic cells represent an essential branch of the immune system, cells have been equipped with a repertoire of signaling molecules that serve to bring about this complex event. Despite the diversity of cell-types and end-purposes that make use of this phenomenon, all phagocytic processes are driven by a finely controlled rearrangement of the actin cytoskeleton to form the phagosome upon activation of specific cell-surface receptors that identify the particle or cell of interest.Multiple receptors simultaneously recognize microbes both through direct binding of microbial surface ligands and by binding to opsonins that have been deposited on the microbial surface. These include: the FcRs(Fc receptors), CRs (complement receptors), non-complement-receptor integrins, lectins and the diverse group of scavenger receptors. In the later case, recognition and binding of microbes by phagocytes is assisted by coating these cells with opsonins, such as complement and Igs (immunoglobulins), that mark them for ingestion and facilitate the process of internalization.Complement-receptor-mediated phagocytosis is morphologically distinct from that mediated by FcRs, although both processes require actin polymerization. Complement-opsonised particles sink into the phagocyte; there is minimal membrane disturbance, and internalization does not usually lead to an inflammatory response or oxidative burst. Internalization by non-complement-receptor integrins such as Alpha5Beta1 and Alpha5Beta3, lectins such as the mannose receptor, the LPS (lipopolysaccharide) receptor CD14 and the scavenger receptors appear to be morphologically dynamic, as in the case of Fc receptors. Membrane is extended around the attached particle, and there is transient membrane ruffling in surrounding areas of the cell. Two members of the scavenger receptor family: SR-A (scavenger receptor-A or macrophage scavenger receptor) and MARCO (macrophage receptor with collagenous structure) have been implicated in binding and internalizing microbes. SR-A is expressed on most macrophages and binds whole bacteria as well as the microbial cell wall components, LTA (lipoteichoic acid) and LPS. The mannose receptor (that binds mannan) and Dectin1 (CLEC7A) (that binds beta-glucan) mediate phagocytosis of yeast and zymosan. Both FN (fibronectin) and VTN (vitronectin) can non-specifically opsonize pathogens.Toll-like receptors (TLRs) are a variety of pattern recognition receptors (PRR) that recognize pathogen associated molecular patterns (PAMP) on infectious agents. Binding of the infectious agents to TLRs stimulates phagocytosis and the release of inflammatory cytokines from the phagocytes. TLRs detect a broad range of microbial products including LPS, PGN (peptidoglycan), and bacterial lipopeptides. Several TLR family members are actively recruited to phagosomes during microbe internalization where they sample the contents of the phagosomes to determine the nature of the microbes being ingested. Dozens of signaling molecules including actin binding proteins, membrane traffic regulators, ion channels, kinases, and lipases are activated during phagocytosis of microbes and may contribute to efficient internalization. Certain signaling molecules stand out both as participating in phagocytosis and as participating in many other signaling pathways. PI3K, PLC (phospholipase-C), RhoGTPases, and PKCs (protein kinase-C) are integration points for regulation of phagocytosis.