S100A9 modulates neutrophil extracellular trap formation thereby enhancing macrophage killing of bacterial pathogens.

Abstract

Abstract Professional phagocytes form the backbone of the innate immune response and are equipped with an arsenal of antimicrobial processes. While many of these processes have been explored in isolation, how immune cells cooperatively combat bacterial pathogens at the site of infection is unclear. The proteins forming calprotectin, S100A8 and S100A9, are the most abundant cytosolic proteins in neutrophils and important components of the innate immune response. Surprisingly, S100A9-deficient (A9−/−) mice are protected from Staphylococcus aureus infection with lower bacterial burdens in the heart. We have uncovered an intracellular function for S100A9, where A9−/− neutrophils produce more mitochondrial superoxide, thereby promoting the terminal formation of neutrophil extracellular traps (suicidal NETosis). Increased suicidal NETosis does not heighten neutrophil killing of S. aureus in isolation, but rather augments macrophage (Mϕ) killing. More specifically, NET formation enhances Mϕ antibacterial activity coinciding with Mϕ phagocytosis of S. aureus and transferring neutrophil-specific antimicrobial peptides to Mϕs. Finally, similar results are observed in response to other phylogenetically distinct bacterial pathogens implicating this as an immune defense mechanism that broadly enhances antibacterial activity. Based on these results, we propose that intracellular S100A9 is a critical rheostat for neutrophil function during infection. Further, NET formation acts as a conduit for neutrophils to enhance the antibacterial activity of Mϕs, where accelerated suicidal NETosis by A9−/− neutrophils makes them especially adept at increasing the antibacterial activity of Mϕs against multiple bacterial pathogens.