Abstract
The phospholipase A2 (PLA2) activity of peroxiredoxin 6 (Prdx6) is required for agonist‐induced NADPH oxidase (Nox2) activation in pulmonary microvascular endothelial cells (PMVEC) and alveolar macrophages (AM). Lysophosphatidylcholine (LPC) is a major product of the PLA2 activity of Prdx6 that it is readily metabolized to lysophosphatidic acid (LPA) by the enzyme autoaxin/lysophospholipase D (ATX/LysoPLD). LPA is a bioactive lipid that signals through G protein‐coupled receptors. LPA receptor activation stimulates pathways regulated by small GTPases, such as the Nox2 cytosolic activator, rac1. We propose that Prdx6PLA2‐derived LPA receptor signaling activates Nox2 in PMVEC and AM. Angiotensin II (Ang II) or phorbol ester (PMA) treatment increased oxidant generation in isolated perfused lungs, PMVEC and AM from WT mice but not in lungs or cells from Nox2 null, Prdx6 null or Prdx6D140A knock‐in mice (which lack Prdx6PLA2 activity). Exogenous LPA restored oxidant generation in Prdx6 null and Prdx6D140A cells. Treatment with the LPA receptor blocker Ki16425 significantly inhibited agonist‐induced oxidant generation in WT lungs and cells and also blocked agonist‐induced rac1 translocation to the plasma membrane in PMVEC. Inhibition of ATX/LysoPLD with HA130 decreased PMA‐ and LPC‐induced oxidant generation in PMVEC; inhibition was reversed by concurrent treatment with LPA. These results suggest that LPA signaling is required for agonist‐induced Nox2 activation and that Prdx6PLA2 likely generates LPC that needs conversion to LPA by ATX/LysoPLD for Nox2 activation. Funded by HL105509.
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