The phospholipase A₂activity of peroxiredoxin 6 modulates NADPH oxidase 2 activationvialysophosphatidic acid receptor signaling in the pulmonary endothelium and alveolar macrophages

Abstract

Peroxiredoxin 6 (Prdx6) is essential for activation of NADPH oxidase type 2 (NOX2) in pulmonary microvascular endothelial cells (PMVECs), alveolar macrophages (AMs), and polymorphonuclear leukocytes. Angiotensin II and phorbol ester increased superoxide/H2O2 generation in PMVECs, AMs, and isolated lungs from wild-type (WT) mice, but had much less effect on cells or lungs from Prdx6-null or Prdx6-D140A-knock-in mice that lack the phospholipase A2 activity (PLA2) of Prdx6; addition of either lysophosphatidylcholine (LPC) or lysophosphatidic acid (LPA) to cells restored their oxidant generation. The generation of LPC by PMVECs required Prdx6-PLA2 We propose that Prdx6-PLA2 modulates NOX2 activation by generation of LPC that is converted to LPA by the lysophospholipase D activity of autotaxin (ATX/lysoPLD). Inhibition of lysoPLD with HA130 (cells,10 μM; lungs, 20 μM; IC50, 29 nM) decreased agonist-induced oxidant generation. LPA stimulates pathways regulated by small GTPases through binding to G-protein-coupled LPA receptors (LPARs). The LPAR blocker Ki16425 (cells, 10 μM; lungs, 25 μM; Ki, 0.34 μM) or cellular knockdown of LPAR type 1 decreased oxidant generation and blocked translocation of rac1 to plasma membrane. Thus, Prdx6-PLA2 modulates NOX2 activation through generation of LPC for conversion to LPA; binding of LPA to LPAR1 signals rac activation.-Vázquez-Medina, J. P., Dodia, C., Weng, L., Mesaros, C., Blair, I. A., Feinstein, S. I., Chatterjee, S., Fisher, A. B. The phospholipase A2 activity of peroxiredoxin 6 modulates NADPH oxidase 2 activation via lysophosphatidic acid receptor signaling in the pulmonary endothelium and alveolar macrophages.

Peroxiredoxin 6 in the repair of peroxidized cell membranes and cell signaling

“…PLA 2 activity results in the generation of lysoPC plus a free fatty acid as its two products. LysoPC is then hydrolyzed to lysophosphatidic acid (LPA) that signals through its receptor leading to activation of rac [146], one of the co-factors (in addition to phosphorylated p47 phox and p67 phox ) that are necessary for NOX2 activation [147] (Fig. 10).…”

“…10). The proteins downstream from Prdx6 that are involved in the rac activation cascade are autotaxin (lysophospholipase D) and LPA receptor 1 (LPAR1), although a possible role for other proteins has not been excluded [146]. …”

“…LysoPC that is generated from PC by the PLA 2 activity of Prdx6 can be metabolized via lysophospholipase D (lysoPLD) to lysophosphatidic acid (lysoPA). Interaction of lysoPA with its receptor (LPAR type 1) leads to release of rac (rac1 or 2 depending on cell type), one of the cytosolic protein co-factors required for NOX2 activation [146]. Other important co-factors for activation include phosphorylated p47 phox and phosphorylated p67 phox .…”

Phospholipase A2 of Peroxiredoxin 6 Plays a Critical Role in Cerebral Ischemia/Reperfusion Inflammatory Injury

“…iPLA2 activity of Prdx6 involved in the TNF-induced apoptosis and the proinflammatory response (Kim et al, 2011). In the pulmonary endothelium and alveolar macrophages, Prdx6-iPLA2 activity modulates NOX2 activation via lysophosphatidic acid receptor signaling (Vázquez-Medina et al, 2016). In this study, our focus was the function of Prdx6-iPLA2 activity in the ischemic brain, which is especially at risk for microglia-mediated neuroinflammatory injury associated with TLR2/4 activation.…”

NM23 proteins: innocent bystanders or local energy boosters for CFTR?

“…For NDPK-A, our own data and that of independent scientists such as K Hallows 86 concur on a bi-directional regulator of NDPK in the context of AMPK's inhibitory role towards CFTR channel function. The other roles of NDPK-A and B in CF pathogenesis need to be determined but we note that NDPK-A has been proposed as a regulator of RAC in relation to the function of epithelial NADPH oxidases [103][104][105] and that NDPK-B is a core regulator of both ligand-independent G protein function and calcium activated potassium channel activity.…”