Phospholipase D mediates Fcγ 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 Fcγ receptor‐mediated mechanism, activating an oxidative burst and initiating degranulation. In contrast, neutrophils exhibit chemotaxis to N ‐formylated peptides [e.g., N ‐formylmethionyl‐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. J. Leukoc. Biol . 61: 522–528; 1997.