Polyisoprenyl phosphate (PIPP) signaling regulates phospholipase D activity: a ‘stop’ signaling switch for aspirin‐triggered lipoxin A₄

Abstract

It is of wide interest to understand how opposing extracellular signals (positive or negative) are translated into intracellular signaling events. Receptor-ligand interactions initiate the generation of bioactive lipids by human neutrophils (PMN), which serve as signals to orchestrate cellular responses important in host defense and inflammation. We recently identified a novel polyisoprenyl phosphate (PIPP) signaling pathway and found that one of its components, presqualene diphosphate (PSDP), is a potent negative intracellular signal in PMN that regulates superoxide anion generation by several stimuli, including phosphatidic acid. We determined intracellular PIPP signaling by autocoids with opposing actions on PMN: leukotriene B4 (LTB4), a potent chemoattractant, and lipoxin A4 (LXA4), a 'stop signal' for recruitment. LTB4 receptor activation initiated a rapid decrease in PSDP levels concurrent with activation of PLD and cellular responses. In sharp contrast, activation of the LXA4 receptor reversed LTB4-initiated PSDP remodeling, leading to an accumulation of PSDP and potent inhibition of both PLD and superoxide anion generation. Thus, an inverse relationship was established for PSDP levels and PLD activity with two PMN ligands that evoke opposing responses. In addition, PSDP directly inhibited both isolated human recombinant (Ki = 6 nM) and plant (Ki = 20 nM) PLD. Together, these findings link PIPP remodeling to intracellular regulation of PMN function and suggest a role for PIPPs as lipid repressors in signal transduction, a novel mechanism that may also explain aspirin's suppressive actions in vivo in cell signaling.

Resolvin E1 regulates interleukin 23, interferon-γ and lipoxin A4 to promote the resolution of allergic airway inflammation

“…Of interest, both RvE1 and LTB 4 can interact with the LTB 4 receptor BLT-1 with RvE1 serving as a receptor antagonist 50 . In addition to its potent pro-resolving signals for airway inflammation 24,47 , LXA 4 can also block LTB 4 -mediated responses in leukocytes 51 . A stable lipoxin analog (ATLa) significantly decreased BALF leukocyte numbers and IL-17 concentrations, but the mechanism by which ATLa promoted resolution was distinct from RvE1-mediated regulation of IL-23 production, suggesting that IL-17 production is downstream of IL-23.…”

Aspirin-Triggered Lipoxins Override the Apoptosis-Delaying Action of Serum Amyloid A in Human Neutrophils: A Novel Mechanism for Resolution of Inflammation

“…It is possible that 15-epi-LXA 4 may generate a yet unidentified negative signal that blocks ERK and Akt. LXA 4 /15-epi-LXA 4 attenuates peroxynitrite signaling (25) via the regulation of presqualene diphosphate accumulation in human PMN (52). LXA 4 /15-epi-LXA 4 through inhibition of PI3K antagonized proliferation of renal mesangial cells (53,54) and human lung fibroblasts (55).…”

A Stable Aspirin-Triggered Lipoxin A4 Analog Blocks Phosphorylation of Leukocyte-Specific Protein 1 in Human Neutrophils

“…Activation of phospholipase D (PLD) is required for the activation of p38-MAPK in neutrophil-like HL-60 cells stimulated with fMLP (53). Intracellular presqualene diphosphate accumulates rapidly in ATLatreated neutrophils stimulated with a chemoattractant and blocks both the activation and activity of PLD (20). Whether ATLa blocks phosphorylation of LSP1 through inhibition of PLD and/or alters the stability of the p38-MAPK phospho-relay complex in neutrophils is currently under investigation.…”