S100A8:S100A9:AA:Ca(2+) binds NOX2 complex

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).

钙离子（Ca(2+)）在吞噬体膜上的通量影响NADPH氧化酶活性和活性氧（ROS）的产生。Fcγ受体（FcγR）或补体受体3（CR3）的吞噬作用激活磷脂酰肌醇-4,5-二磷酸3-激酶（PI3K），进而导致PI(3,4,5)P3的形成。该磷脂参与磷脂酶γC（PLCγ）和磷脂酶D（PLD）介导的下游信号通路激活。PLCγ生成的IP3通过IP3受体（IP3-R）的开放，触发细胞内储存（内质网，ER）中钙离子的释放。PLD参与鞘氨醇激酶产生的鞘氨醇1-磷酸（S1P）的过程，导致细胞内钙离子储存的耗竭。细胞内钙离子储存的耗竭诱导钙离子传感器间质相互作用分子-1（STIM1）的激活，进而激活位于质膜和细胞外空间的钙离子释放激活钙通道蛋白1（ORAI1），导致钙离子的跨膜进入。结果升高的钙离子介导细胞质中钙离子激活的调节因子S100A8（亦称为迁移抑制因子相关蛋白8（MRP8））和S100A9（MRP14）向吞噬体膜的募集（Berthier S等，2003，2012；Steinckwich N等，2011；Bréchard S等，2013）。S100A8:S100A9的转位允许S100A9结合的二十碳四烯酸（AA）转移到细胞色素b558，有利于细胞色素b558构象的改变，并促进吞噬体内NADPH氧化酶的活化和ROS的产生（Berthier S等，2003，2012；Doussiere J et L.，2002；Kerkhoff C等，2005；Steinckwich N等，2011；Bréchard S等，2013）。S100A8和S100A9主要以S100A8:S100A9异二聚体的形式存在，根据其在先天免疫中的作用被称为钙保护蛋白（Korndorfer IP等，2007）。钙离子还已知可刺激S100蛋白的高阶寡聚体的形成，包括S100A8/S100A9四聚体（Leukert N等，2006；Korndörfer IP等，2007）。此外，钙保护蛋白已被证明可以通过螯合细胞外锰Mn(2+)、锌Zn(2+)以及可能铁Fe(2+)来抑制细菌生长，从而限制感染期间金属离子的可用性（Damo SM等，2013；Hayden JA等，2013；Brophy MB等，2013；Gagnon DM等，2015）。