15-Epi-lipoxin A4 inhibits human neutrophil superoxide anion generation by regulating polyisoprenyl diphosphate phosphatase 1

Regulation of leukocyte activation is critical to limit unintended tissue injury during acute inflammation. On neutrophil activation, polyisoprenyl diphosphate phosphatase 1 (PDP1) rapidly converts presqualene diphosphate to presqualene monophosphate to facilitate cell activation. Lipoxins are potent anti-inflammatory mediators for neutrophils, yet their counterregulatory signaling mechanisms remain to be determined. 15-Epi-lipoxin A(4) (15-epi-LXA(4)) blocked agonist-initiated association of the nicotinamide adenine dinucleotide phosphate oxidase components p47(PHOX) and p22(PHOX) in human neutrophils. 15-Epi-LXA(4) (0.1-100 nM) inhibited neutrophil superoxide anion (O-2(-)) generation in a concentration- and ALX/FPR2 receptor-dependent manner that was disrupted by PDP1-specific antibodies. In differentiated HL60 cells, a myeloid cell line, agonist-initiated O-2(-) generation was inhibited by PDP1 siRNA. Recombinant human PDP1 was directly phosphorylated in vitro by select protein kinase C (PKC) isoforms, including PKCII. When neutrophils were exposed to formyl-methionyl-leucyl-phenylalanine (fMLP), PKCII was rapidly phosphorylated and physically associated with PDP1. Agonist-initiated conversion of neutrophil presqualene diphosphate to presqualene monophosphate was blocked by PKCII inhibition. Neutrophil exposure to 15-epi-LXA(4) attenuated fMLP triggered PKCII phosphorylation and its interactions with PDP1. Together, these findings indicate that PDP1 serves an integral signaling role in neutrophil proinflammatory responses and as a target for counter-regulatory mediators.Carlo, T., Kalwa, H., Levy, B. D. 15-Epi-lipoxin A(4) inhibits human neutrophil superoxide anion generation by regulating polyisoprenyl diphosphate phosphatase 1.