Human IgA Fc Receptor FcαRI (CD89) Triggers Different Forms of Neutrophil Death Depending on the Inflammatory Microenvironment

Fc alpha RI (CD89), the human Fc receptor for IgA, is highly expressed on neutrophil granulocytes. In this study, we show that FcaRI induces different forms of neutrophil death, depending on the inflammatory microenvironment. The susceptibility of inflammatory neutrophils from sepsis or rheumatoid arthritis toward death induced by specific mAb, or soluble IgA at high concentrations, was enhanced. Although unstimulated cells experienced apoptosis following anti-Fc alpha RI mAb stimulation, preactivation with cytokines or TLR agonists in vitro enhanced Fc alpha RI-mediated death by additional recruitment of caspase-independent pathways, but this required PI3K class IA and MAPK signaling. Transmission electron microscopy of Fc alpha RI-stimulated cells revealed cytoplasmic changes with vacuolization and mitochondrial swelling, nuclear condensation, and sustained plasma membrane. Coculture experiments with macrophages revealed anti-inflammatory effects of the partially caspase-independent death of primed cells following Fc alpha RI engagement. Our data suggest that Fc alpha RI has the ability to regulate neutrophil viability and to induce different forms of neutrophils depending on the inflammatory microenvironment and specific characteristics of the ligand-receptor interactions. Furthermore, these findings have potential implications for Fc alpha RI-targeted strategies to treat neutrophil-associated inflammatory diseases.