Neutrophil effector responses are suppressed by secretory phospholipase A2 modified HDL

Secretory phospholipase A(2) (sPLA(2)) generates bioactive lysophospholipids implicated in acute and chronic inflammation, but the pathophysiologic role of sPLA(2) is poorly understood. Given that high-density lipoprotein (HDL) is the major substrate for sPLA(2) in plasma, we investigated the effects of sPLA(2)-mediated modification of HDL (sPLA(2)-HDL) on neutrophil function, an essential arm of the innate immune response and atherosclerosis. Treatment of neutrophils with sPLA(2)-HDL rapidly prevented agonist-induced neutrophil activation, including shape change, neutrophil extracellular trap formation, CD11b activation, adhesion under flow and migration of neutrophils. The cholesterol-mobilizing activity of sPLA(2)-HDL was markedly increased when compared to native HDL, promoting a significant reduction of cholesterol-rich signaling microdomains integral to cellular signaling pathways. Moreover, sPLA(2)-HDL effectively suppressed agonist-induced rise in intracellular Ca2+ levels. Native HDL showed no significant effects and removing lysophospholipids from sPLA(2)-HDL abolished all anti-inflammatory activities. Overall, our studies suggest that the increased cholesterol-mobilizing activity of sPLA(2)-HDL and suppression of rise in intracellular Ca2+ levels are likely mechanism that counteracts agonist-induced activation of neutrophils. These counterintuitive findings imply that neutrophil trafficking and effector responses are altered by sPLA(2)-HDL during inflammatory conditions. (C) 2014 Elsevier B.V. All rights reserved.