The role of calcium signaling in phagocytosis

Abstract

Immune cells kill microbes by engulfing them in a membrane-enclosed compartment, the phagosome. Phagocytosis is initiated when foreign particles bind to receptors on the membrane of phagocytes. The best-studied phagocytic receptors, those for Igs (FcgammaR) and for complement proteins (CR), activate PLC and PLD, resulting in the intracellular production of the Ca(2+)-mobilizing second messengers InsP3 and S1P, respectively. The ensuing release of Ca(2+) from the ER activates SOCE channels in the plasma and/or phagosomal membrane, leading to sustained or oscillatory elevations in cytosolic Ca(2+) concentration. Cytosolic Ca(2+) elevations are required for efficient ingestion of foreign particles by some, but not all, phagocytic receptors and stringently control the subsequent steps involved in the maturation of phagosomes. Ca(2+) is required for the solubilization of the actin meshwork that surrounds nascent phagosomes, for the fusion of phagosomes with granules containing lytic enzymes, and for the assembly and activation of the superoxide-generating NADPH oxidase complex. Furthermore, Ca(2+) entry only occurs at physiological voltages and therefore, requires the activity of proton channels that counteract the depolarizing action of the phagocytic oxidase. The molecules that mediate Ca(2+) ion flux across the phagosomal membrane are still unknown but likely include the ubiquitous SOCE channels and possibly other types of Ca(2+) channels such as LGCC and VGCC. Understanding the molecular basis of the Ca(2+) signals that control phagocytosis might provide new, therapeutic tools against pathogens that subvert phagocytic killing.

Stimulation of Unprimed Macrophages with Immune Complexes Triggers a Low Output of Nitric Oxide by Calcium-dependent Neuronal Nitric-oxide Synthase

“…The importance of Ca 2ϩ flux from endoplasmic reticulum stores during Fc␥R-induced phagocytosis was clearly shown using STIM1 KO macrophages (42), and our findings are consistent with these data. Some have suggested that Ca 2ϩ is not as important for phagocytosis of particles, but more important for the subsequent steps of phagosomal maturation (43). However, the data involving STIM1 KO macrophages and our data with SelK KO macrophages do not support this notion.…”

A novel Plasmodium-specific prodomain fold regulates the malaria drug target SUB1 subtilase

“…Calcium ions are ubiquitous and versatile signalling molecules that play pleiotropic roles in the complex cellular organization and life cycle [38][39][40][41][42] , including during the egress from and the subsequent invasion of host cells by Apicomplexan parasites 25,[43][44][45] . The secretion route of eukaryotic cells has a gradient of Ca 2 þ concentration ([Ca 2 þ ]), being high in the ER (up to 400 mM), decreasing through the Golgi apparatus (250-130 mM) to reach values lower than 100 mM within secretory vesicles 38 .…”

A C2 domain protein kinase initiates phagocytosis in the protozoan parasite Entamoeba histolytica

“…In the presence of PI3K inhibitors, incomplete phagosomes appear as actin-rich phagocytic cups, suggesting that PI3K may be involved in organizing the later stages of phagocytosis [13][14][15] . Ca 2 + signals are generated subsequent to the activation of FcγR through downstream processes that involve activation of PLCγ and are required for phagosome closure and maturation mainly through actin remodeling 16 . It is not clear whether Ca 2 + signalling has any role in the process of initiation.…”