Fc-GammaR-Mediated Phagocytosis in Macrophages
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Fc-GammaR-Mediated Phagocytosis in Macrophages

Phagocytosis is of fundamental importance for a wide diversity of organisms. Phagocytic cells in complex metazoans represent an essential branch of the immune system. Evolution has armed these cells with a fantastic repertoire of receptors and molecules that serve to bring about this complex event (Ref.1). In macrophages, different cell surface receptors stimulate different kinds of phagocytic response. Macrophage Fc-Gamma-Rs (Fc-Gamma Receptors) play a key role in immune defenses by mediating prompt clearance of IgG (Immunoglobulin-G)-coated foreign particles from the organism by the process of phagocytosis (Ref.2). IgGs act as Opsonins, molecules that render the particle they coat more susceptible to engulfment by the phagocytes. The conserved Fc (Crystalline Fragment) domains of the IgGs are recognised by Fc-Gamma-Rs present on macrophages, and the opsonised particle is rapidly internalized by pseudopod extension. This internalisation can be considered a morphogenetic process, in which the actin cytoskeleton is reorganized into a cup-shaped, cell surface protrusion that constricts at its outer margin to form an enclosure, termed as Phagosome (Ref.3). 

A range of Fc-Gamma-Rs exist in macrophages. High affinity (Fc-GammaRI) and low affinity (Fc-GammaRIIA and Fc-GammaRIIIA) Fc-Gamma-Rs bind to IgG-Opsonized particles and trigger internalization through actin Polymerization beneath the particle followed by membrane recruitment to the site of particle contact, membrane extension outward to surround the particle, and particle engulfment (Ref.4). This internalisation is followed by secondary activity, such as the production of Superoxides and the release of pro-inflammatory mediators (Ref.2). Fc-GammaRIIB (an isoform of Fc-GammaRIIA), negatively regulates phagocytosis, unless its cytoplasmic tail is mutated to resemble that of Fc-GammaRIIA, when it becomes phagocytic. Fc-Gamma-Rs signal phagocytosis via their phosphorylated ITAM (Immunoglobulin Tyrosine Activation Motif) domains. The interaction between Fc-GammaR and the Fc region of IgG upon the Opsonised particle triggers rapid phosphorylation of specific tyrosine residues in the receptor within the ITAM motifs. Receptor cross-linking stimulates Src Family Kinases to phosphorylate Tyrosine (Y) residues within the ITAM domain of Fc-GammaRIIA whereas the relevant ITAMs for Fc-GammaRI and Fc-GammaRIIIA are contained within a separate molecule, the dimmeric Gammaƒn-subunit, which associates with the receptor (Ref.1). The initial interaction between an Fc-GammaR and IgG upon the particle tethers the target to the membrane. Other Fc-Gamma-Rs are subsequently recruited to the target, leading to zippering as they sequentially engage with ligands on the particle. Zippering drives the initial extension of membrane around the particle in a process that does not require actin polymerization or signaling from the cytoplasmic domain of the receptor, at least for Fc-GammaRIA. Active signalling from the receptor leads to the recruitment of numerous cytoskeletal proteins, including the ARP2/3 (ARP2 (Actin-Related Protein-2)/(Actin-Related Protein-3)) Complex, which nucleates actin filaments beneath the particle. The formation of a network pushes the plasma membrane further around the target. Once most of the particle is within the cell, PI3K (Phosphatidylinositde-3 Kinase) activity leads to the final engulfment through vesicle recycling; or, through a myosin-based contractile activity (Ref.5).

The initial Tyrosine phosphorylation event is carried out by members of the Src Family: HCK (Hemopoietic Cell Kinase) and Lyn (V-YES-1 Yamaguchi Sarcoma Viral Related Oncogene Homolog) which phosphorylate the receptor (or associated Gamma-subunit). In contrast, Fgr (Oncogene Fgr) negatively regulates phagocytosis by activating the phosphatase SHP1 (Tyrosine Phosphatase Shp1). The Tyrosine kinase SYK (Spleen Tyrosine Kinase) is then recruited to the phosphorylated ITAM domain, where it is activated. SYK is also capable of autoactivation. Active SYK then transmits downstream signals leading to actin polymerisation and particle internalisation (Ref.6). SYK is clearly a critical component for Fc-GammaR signaling, since macrophages lacking SYK cannot internalise IgG-opsonised particles. In addition to SYK and Src-family Kinases, Fc-Gamma-R stimulation activates PYK2 (Proline-Rich Tyrosine Kinase-2), which facilitates actin reorganization and recruitment of several cytoskeletal components to the nascent phagosome (Ref.7). Among downstream effectors of the tyrosine kinases are PI3K, PLC (Phospholipase-C) and monomeric GTPases. Polymerization of actin and formation of phagosomes is brought about by the participation of PI3K, the Rho family of GTPases, PKC (Protein Kinase-C), and Motor proteins. PI3K catalyzes phosphorylation at the D-3 position of the Inositol ring of PI (Phosphatidylinositol), PIP (Phosphatidylinositol Phosphate) and PIP2 (Phosphatidylinositol 4,5-bisphosphate) leading to subsequent production of PIP3 (Phosphatidylinositol 3,4,5-trisphosphate). Cross-linking of Fc-GammaRI and Fc-GammaRII increases PI3K activity. Various members of the Rho family, activated by Vav, act hierarchically during phagocytosis: CDC42 (Cell Division Cycle-42) partipates in the formation of filopodia and in the activation of Rac; Rac stimulates membrane ruffling and activates Rho, and Rho stimulates the formation of focal adhesions and stress fibers. Vav is activated by Src Family Kinases. PIP5K (Phosphatidylinositol 4-Phosphate 5-Kinase) and Myosin-II have also been implicated in the process. PIP5K activation leads to a local increase of PIP2 level. Under the influence of PIP2, proteins like Gelsolin uncap actin filaments, whereas Profilin provides actin monomers required for filament elongation through G-actin. Vcl(Vinculin), Pxn (Paxillin), Alpha-Actin, can participate in a spatial organization of polymerized microfilaments (Ref.6). ARF6 (ADP-Ribosylation Factor-6) has also been implicated in endocytosis, membrane recycling and regulated exocytosis (Ref.3). PLC is activated in human macrophages upon ligation of the Fc-Gamma-Rs , followed by activation of IP3 (Inositol 1,4,5-trisphosphate) and Ca2+ (Calcium) release. PLC activates DAG (Diacylglycerol), which triggers localization of PKC-Alpha (Protein Kinase-C-Alpha) to nascent Phagosomes (Ref.5). Sometimes, Motor proteins participate in the process of pseudopod extension and particle internalization. Myosin-I, Myosin-V, and Myosin-IX colocalize with F-actin on forming phagosomes. All these events culminate in actin Nucleation, Reorganization and the subsequent Membrane Extension. This dramatic, actin-dependent extension of the plasma membrane around the particle is followed by secondary activity, such as the production of Superoxide and the release of inflammatory cytokines from the phagocyte, an important component of the immune response (Ref.6).

The elimination of the invading pathogens and other harmful foreign particles is an important component of the immune system. In the absence of a working immune system, even minor infections can take hold and prove fatal. In this regard, macrophages are a cornerstone of the innate immune system. They detect infectious organisms via a plethora of receptors, phagocytose them, and orchestrate an appropriate host response (Ref.5). Phagocytosis by macrophages by Fc-Gamma-Rs is critical for the uptake and degradation of infectious agents and senescent cells, and it also participates in development, tissue remodeling, the immune response, and inflammation (Ref.4).