Ca(2+) flux across the phagosomal membrane influences NADPH oxidase activity and ROS production. Phagocytic engagement of Fc gamma receptor (FcγR) or complement receptor 3 (CR3) activate phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), leading to the formation of PI(3,4,5)P3. This phospholipid participates in the activation of phospholipase γ C (PLCγ) and phospholipase D (PLD)-mediated downstream signaling pathways. The generation of IP3 by PLCγ triggers Ca(2+) release from intracellular stores (endoplasmic reticulum, ER) via the opening of IP3 receptors (IP3-R). PLD is involved in the process of sphingosine kinase-produced sphingosine 1-phosphate (S1P), leading to the depletion of intracellular Ca(2+) stores. The emptying of intracellular Ca2+ stores induces the activation of the Ca(2+) sensor stromal interaction molecule-1 (STIM1), which, in turn, activates calcium release-activated calcium channel protein 1 (ORAI1) at the plasma membrane and extracellular Ca(2+) entry. The resulting elevation of Ca(2+) mediates the recruitment of the cytosolic Ca(2+)-activated regulators S100A8 (also know as migration inhibitory factor-related proteins 8 (MRP8)) and S100A9 (MRP14) to the phagosomal membrane (Berthier S et al. 2003, 2012; Steinckwich N et al. 2011; Bréchard S et al. 2013). The translocation of S100A8:S100A9 allows the transfer of S100A9-binding arachidonic acid (AA) to cytochrome b558, favoring the conformational change of cytochrome b558 and promoting intraphagosomal NADPH oxidase activation and ROS production (Berthier S et al. 2003, 2012; Doussiere J et L. 2002; Kerkhoff C et al. 2005; Steinckwich N et al. 2011; Bréchard S et al. 2013 ). S100A8 & S100A9 exist mainly as a S100A8:S100A9 heterodimer which is termed calprotectin based on its role in innate immunity (Korndorfer IP et al. 2007). Ca(2+) is also known to stimulate formation of higher order oligomers of S100 proteins, including S100A8/S100A9 tetramers (Leukert N et al. 2006; Korndörfer IP et al. 2007). In addition, calprotectin has been shown to inhibit bacterial growth through chelation of extracellular manganese Mn(2+), zinc Zn(2+) and possibly iron Fe(2+) and thus restricting metal-ion availability during infection (Damo SM et al. 2013; Hayden JA et al. 2013; Brophy MB et al. 2013; Gagnon DM et al. 2015).