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 gamma receptor-mediated mechanism, activating an oxidative burst and initiating 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 neutrophils activated by HIC. However, if neutrophils are treated with cytochalasin B (CB) or permeabilized with streptolysin O, chemoattractant-induced neutrophil secretion is increased to a level beyond that observed in response to HIC. Because priming neutrophils with CB, or permeabilizing them, also augments activation of phospholipase D (PLD) in response to fMLP, we reasoned that, in intact (i.e., nonpermeabilized) unprimed neutrophils, PLD may participate in a signaling pathway specific to phagocytic stimuli such as HIC and hence may contribute to degranulation control. PLD activity in response to HIC and fMLP correlated closely with stimulus-induced azurophilic degranulation under a wide variety of experimental conditions, including compounds that abrogated or augmented stimulus-induced PLD action. PLD activation preceded, and appeared to be necessary for, azurophilic degranulation. These results suggest that PLD may play a central role in controlling azurophilic degranulation and provide signaling specificity between pathways activated by fMLP and HIC in intact neutrophils.