title: Neutrophil effector responses are suppressed by secretory phospholipase A2 modified HDL.
abstract: Secretory phospholipase A2 (sPLA2) generates bioactive lysophospholipids implicated in acute and chronic inflammation, but the pathophysiologic role of sPLA2 is poorly understood. Given that high-density lipoprotein (HDL) is the major substrate for sPLA2 in plasma, we investigated the effects of sPLA2-mediated modification of HDL (sPLA2-HDL) on neutrophil function, an essential arm of the innate immune response and atherosclerosis. Treatment of neutrophils with sPLA2-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 sPLA2-HDL was markedly increased when compared to native HDL, promoting a significant reduction of cholesterol-rich signaling microdomains integral to cellular signaling pathways. Moreover, sPLA2-HDL effectively suppressed agonist-induced rise in intracellular Ca²⁺ levels. Native HDL showed no significant effects and removing lysophospholipids from sPLA2-HDL abolished all anti-inflammatory activities. Overall, our studies suggest that the increased cholesterol-mobilizing activity of sPLA2-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 sPLA2-HDL during inflammatory conditions.
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Austria.
authors.forename: Sanja
authors.initials: S
authors.lastname: Curcic
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Holzer
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Austria.
authors.forename: Robert
authors.initials: R
authors.lastname: Frei
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Austria.
authors.forename: Lisa
authors.initials: L
authors.lastname: Pasterk
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Austria.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Schicho
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Austria.
authors.forename: Akos
authors.initials: A
authors.lastname: Heinemann
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Austria. Electronic address: gunther.marsche@medunigraz.at.
authors.forename: Gunther
authors.initials: G
authors.lastname: Marsche
mesh_terms: D039481:CD11b Antigen / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002448:Cell Adhesion; D048430:Cell Shape; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte; D008076:Cholesterol, HDL / Q000378:metabolism*; D065206:Extracellular Traps / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D007155:Immunologic Factors / Q000494:pharmacology; D008244:Lysophosphatidylcholines / Q000378:metabolism; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D054497:Phospholipases A2, Secretory / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D039481:CD11b Antigen; D008076:Cholesterol, HDL; C509295:ITGAM protein, human; D007155:Immunologic Factors; D008244:Lysophosphatidylcholines; D054497:Phospholipases A2, Secretory; D002118:Calcium
keywords: HDL; Lysophospholipid; Neutrophil; Secretory phospholipase A(2)