PHOSPHOLIPASE-D MEDIATES FC-GAMMA RECEPTOR ACTIVATION OF NEUTROPHILS AND PROVIDES SPECIFICITY BETWEEN HIGH-VALENCY IMMUNE-COMPLEXES AND FMLP SIGNALING PATHWAYS

Neutrophils phagocytize high-valency immune complexes (HIC) by an Fc g amma receptor-mediated mechanism, activating an oxidative burst and in itiating degranulation. In contrast, neutrophils exhibit chemotaxis to N-formylated peptides [e.g., N-formyl-methionyl-leucyl-phenylalanine (fMLP)] and secrete far fewer oxidants or granule contents than neutro phils activated by HIC. However if neutrophils are treated with cytoch alasin B (CB) or permeabilized with streptolysin O, chemoattractant-in duced neutrophil secretion is increased to a level beyond that observe d in response to HIC. Because priming neutrophils with CB, or permeabi lizing them, also augments activation of phospholipase D (PLD) in resp onse to fMLP, we reasoned that, in intact (i.e., nonpermeabilized) unp rimed neutrophils, PLD may participate in a signaling pathway specific to phagocytic stimuli such as HIC and hence may contribute to degranu lation control. PLD activity in response to HIC and fMLP correlated cl osely with stimulus-induced azurophilic degranulation under a wide var iety of experimental conditions, including compounds that abrogated or augmented stimulus-induced PLD action. PLD activation preceded, and a ppeared to be necessary for, azurophilic degranulation. These results suggest that. PLD may play a central role in controlling azurophilic d egranulation and provide signaling specificity between pathways activa ted by fMLP and HIC in intact neutrophils.