Fcγ Receptor-mediated Phagocytosis in Macrophages and Monocytes

Phagocytosis is a host cell endocytic response to particulate matter like bacteria. Avidly phagocytic cells, like macrophages and neutrophils, are an early line of defense against invading bacteria. The process of phagocytosis is complex and comprises of several events like particle binding, receptor clustering, actin nucleation, pseudopod extension, membrane recycling and phagosome closure. The Fc gamma receptors (FcγR; subtypes FcγR1A, FcγRIIA and FcγRIIIA) of the immunoglobulin superfamily are the best characterized receptors for phagocytosis in macrophages and monocytes. The activated receptors signal via immunoreceptor based tyrosine activation motifs (ITAM) which are present either in the cytosolic domain of the receptor (FcγRIIA) , in an associated γ(FcγR1A and FcγRIIIA) or ζ (FcγIIIA) subunit.Binding of IgG opsonized particles to the FcγR results in its activation and tyrosine phosphorylation of the associated ITAM.This phosphorylation is probably mediated by members of the SRC kinase family like FGR. Phosphorylated ITAM creates a binding site for the SRC kinase members like LYN and HCK and the spleen tyrosine kinase (SYK). It is thought that many downstream effectors are triggered by these kinases. Actin assembly is a crucial early step in phagocytosis and is triggered by G proteins like RAC and cell division cycle 42 protein (CDC42) by the activation of the actin related protein 2/3 (ARP2/3) complex and p21 activated kinase (PAK1). RAC in turn can be activated by the guanine nucleotide exchange factor (GEF) DOCK180 and adaptor protein CRKII. Other important promoters of actin assembly include ADP-ribosylation factor 6 (ARF6), protein kinase B (PKB/AKT) and protein tyrosine kinase 2 beta (PYK2). Local polymerization of actin filaments is required for the protrusion of pseudopodia that eventually internalize the particle. A large molecular complex consisting in part of vasodilator-stimulated phosphoprotein (VASP), the Fyn-binding/SLP-76-associated protein (FYB/SLAP), Src-homology-2 (SH2)-domain-containing leukocyte protein of 76 kD (SLP-76), non-catalytic region of tyrosine kinase (NCK), and the Wiskott-Aldrich syndrome protein (WASP) is recruited to the nascent phagosome and plays a crucial role in actin polymerization and pseudopod extension. In addition to actin, structural proteins like talin, ezrin and myosin are also recruited to the nascent phagosome.Phagosome closure and particle internalization are important steps towards the formation of the mature phagosome. Phosphoinositide 3 kinase (PI3K), a down stream target of SYK, participates in nascent phagosome closure; this PI3K signal is amplified by Grb2 associated binder 2 (GAB2). Another target of FcγR activation is protein kinase C (PKC), which via the activation of phospholipase C A2 (PLC-A2) and formation of arachidonic acid, promotes phagosome closure and membrane fusion. Several other FcγR activated proteins play key roles in the formation of the mature phagosome: e.g. phospholipase C gamma 1 (PLC-γ1) and phospholipase D (PLD) in particle internalization; G protein RAB11 and vesicle-associated membrane protein 3 (VAMP3) in membrane recycling and remodeling. Structural proteins that are associated with the mature, actin depleted phagosome include myosin and ezrin.This pathway highlights the important molecular events during FcγR activation in macrophages and monocytes.