How Important are S100A8/S100A9 Calcium Binding Proteins for the Activation of Phagocyte NADPH Oxidase, Nox2

S100A8 and S100A9 are two soluble calcium-binding proteins highly expressed in myeloid cells, mainly neutrophils (45% of cytosolic proteins) or monocytes (1-5%) and also early differentiated macrophages. In neutrophils, they are believed to be expressed as a 1/1 non covalent heterodimer; the process of dimer and mainly tetramer formation is calcium dependent. The S100A8/S100A9 calcium loaded complex binds arachidonic acid and shuttles between cytosol and plasma membrane upon neutrophil stimulation. Neutrophils display, upon stimulation, a respiratory burst in which the cells catalyze NADPH oxidase activity through a redox membrane hemoprotein, cytochrome b558, which is constituted of 2 subunits: gp91-phox, the redox core and p22- phox the stabilizing partner. In neutrophils, this activity is transitory: to be active, regulatory cytosolic factors, p67-phox, p47-phox, p40-phox and Rac1/2 assemble with membrane cytochrome b558. Both S100A8 and S100A9 were recently introduced as partners for NADPH oxidase activation and associate with the cytosolic activating factors especially p67-phox and Rac1/2. Moreover, S100A8/S100A9 potentiates NADPH oxidase activity. This was observed ex vivo after co-transfection of genes encoding both S100A8 and S100A9 in B lymphocytes that express all the components of the phagocyte oxidase, but display a very low NADPH oxidase activity (in these cells, S100A8 and S100A9 are not present endogenously). In the biological function of S100A8/S100A9, S100A8 is a strategic protein that needs to be active in vivo as in vitro, its specific partner S100A9. New data introduce S100A8 and S100A9 as positive effectors in allosteric regulation of phagocyte NADPH oxidase activity.