Lipoxins control neutrophil superoxide anion production by regulation of polyisoprenyl diphosphate phosphatase 1 activity

Abstract

In health, pro‐resolving signals are produced to facilitate the successful termination of inflammatory responses. Lipoxins (LXs) are agonists of resolution that block the actions of neutrophils (PMNs). Located in PMN cell membranes, presqualene diphosphate (PSDP) acts as an intracellular signaling molecule that inhibits superoxide anion (O2−) production. Polyisoprenyl diphosphate phosphatase 1 (PDP1) is a lipid phosphate phosphatase that remodels cellular PSDP to its monophosphate form in response to agonists. Here, we present evidence, in human leukocytes, of an intracellular signal cascade with PDP1 that can respond to both pro‐inflammatory and counter‐regulatory signals as a molecular switch controlling the activation state of human PMNs. Exposure of human PMNs to 15‐epi‐LXA4 and transfection of PMN‐like HL60 cells with PDP1 siRNA led to decreased NADPH oxidase assembly and O2−. Of note, transfection of freshly isolated human PMNs with PDP1‐specific antibodies led to decreased O2− generation and potently blocked 15‐epi‐LXA4‐ mediated inhibition of PMN responses. PDP1 was phosphorylated in vitro by protein kinase C betaII (PKCbetaII) and inhibitors of PKCbetaII block PSDP remodeling and PMN O2− generation. Exposing PMNs to 15‐epi‐LXA4 inhibited agonist dependent PKCbetaII phosphorylation and its association with PDP1. Together, these findings suggest a critical role for PDP1 in PMN activation.