Neutrophils play a central role in host defense, inflammation, and tissue injury. Recent findings indicate a novel role for polyisoprenyl phosphates (PIPPs) as natural down-regulatory signals in neutrophils. The relationship between PIPPs and neutrophil early activating signals, such as phosphoinositides, has not been previously determined. Here, we establish presqualene diphosphate (PSDP) as an endogenous PIPP regulator of phosphatidylinositol 3-kinase (PI3K). In human neutrophils, leukotriene B 4 (LTB 4) triggered rapid decreases in PSDP and reciprocal increases in PI3K activity. In addition, PSDP was identified by gas chromatography/mass spectrometry in p110γ-PI3K immunoprecipitates obtained 30 s after LTB 4, indicating a physical interaction between PSDP and PI3K in activated neutrophils. Moreover, PSDP (0.4-800 pmol) directly inhibited recombinant human p110γ-PI3K activity. During an experimental model of lung injury and inflammation, a reciprocal relationship was also present in vivo for lung PSDP and PI3K activity. To investigate its therapeutic potential, we developed a new PSDP structural mimetic that blocked human neutrophil activation and mouse lung PI3K activity and inflammation. Together, our findings indicate that PSDP is an endogenous PI3K inhibitor, and suggest that in inflammatory diseases characterized by excessive neutrophil activation, PIPPs can serve as structural templates in a novel antineutrophil therapeutic strategy to limit tissue injury.
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