title: Polarization of Macrophages toward M2 Phenotype Is Favored by Reduction in iPLA2β (Group VIA Phospholipase A2).
abstract: Macrophages are important in innate and adaptive immunity. Macrophage participation in inflammation or tissue repair is directed by various extracellular signals and mediated by multiple intracellular pathways. Activation of group VIA phospholipase A2(iPLA2β) causes accumulation of arachidonic acid, lysophospholipids, and eicosanoids that can promote inflammation and pathologic states. We examined the role of iPLA2β in peritoneal macrophage immune function by comparing wild type (WT) and iPLA2β-/-mouse macrophages. Compared with WT, iPLA2β-/-macrophages exhibited reduced proinflammatory M1 markers when classically activated. In contrast, anti-inflammatory M2 markers were elevated under naïve conditions and induced to higher levels by alternative activation in iPLA2β-/-macrophages compared with WT. Induction of eicosanoid (12-lipoxygenase (12-LO) and cyclooxygenase 2 (COX2))- and reactive oxygen species (NADPH oxidase 4 (NOX4))-generating enzymes by classical activation pathways was also blunted in iPLA2β-/-macrophages compared with WT. The effects of inhibitors of iPLA2β, COX2, or 12-LO to reduce M1 polarization were greater than those to enhance M2 polarization. Certain lipids (lysophosphatidylcholine, lysophosphatidic acid, and prostaglandin E2) recapitulated M1 phenotype in iPLA2β-/-macrophages, but none tested promoted M2 phenotype. These findings suggest that (a) lipids generated by iPLA2β and subsequently oxidized by cyclooxygenase and 12-LO favor macrophage inflammatory M1 polarization, and (b) the absence of iPLA2β promotes macrophage M2 polarization. Reducing macrophage iPLA2β activity and thereby attenuating macrophage M1 polarization might cause a shift from an inflammatory to a recovery/repair milieu.
authors.affiliation: From the Department of Biology, Eastern Washington University, Cheney, Washington 99004.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Ashley
authors.affiliation: Department of Cell, Developmental, and Integrative Biology.|Comprehensive Diabetes Center, and.
authors.forename: William D
authors.initials: WD
authors.lastname: Hancock
authors.affiliation: Department of Cell, Developmental, and Integrative Biology.|Comprehensive Diabetes Center, and.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Nelson
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, and.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Bone
authors.affiliation: Comprehensive Diabetes Center, and.|Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Hubert M
authors.initials: HM
authors.lastname: Tse
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: Mary
authors.initials: M
authors.lastname: Wohltmann
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: John
authors.initials: J
authors.lastname: Turk
authors.affiliation: Department of Cell, Developmental, and Integrative Biology, sramvem@uab.edu.|Comprehensive Diabetes Center, and.
authors.forename: Sasanka
authors.initials: S
authors.lastname: Ramanadham
mesh_terms: D000818:Animals; D016764:Cell Polarity; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000276:immunology; D005260:Female; D054522:Group VI Phospholipases A2 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000166:cytology* / Q000201:enzymology / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000276:immunology
chemical_list: D051546:Cyclooxygenase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; D054522:Group VI Phospholipases A2; C516476:Pla2g6 protein, mouse
keywords: Phospholipase A2; alternative activation; autoimmune disease; classical activation; eicosanoids; inflammation; macrophage; phospholipase; phospholipid; polarization