title: Phospholipid oxidation generates potent anti-inflammatory lipid mediators that mimic structurally related pro-resolving eicosanoids by activating Nrf2.
abstract: Exposure of biological membranes to reactive oxygen species creates a complex mixture of distinct oxidized phospholipid (OxPL) species, which contribute to the development of chronic inflammatory diseases and metabolic disorders. While the ability of OxPL to modulate biological processes is increasingly recognized, the nature of the biologically active OxPL species and the molecular mechanisms underlying their signaling remain largely unknown. We have employed a combination of mass spectrometry, synthetic chemistry, and immunobiology approaches to characterize the OxPL generated from the abundant phospholipid 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (PAPC) and investigated their bioactivities and signaling pathways in vitro and in vivo. Our study defines epoxycyclopentenones as potent anti-inflammatory lipid mediators that mimic the signaling of endogenous, pro-resolving prostanoids by activating the transcription factor nuclear factor E2-related factor 2 (Nrf2). Using a library of OxPL variants, we identified a synthetic OxPL derivative, which alleviated endotoxin-induced lung injury and inhibited development of pro-inflammatory T helper (Th) 1 cells. These findings provide a molecular basis for the negative regulation of inflammation by lipid peroxidation products and propose a novel class of highly bioactive compounds for the treatment of inflammatory diseases.
authors.affiliation: Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Bretscher
authors.affiliation: Laboratory of Organic Chemistry, Department of Chemistry, ETH Zurich, Zurich, Switzerland.
authors.forename: Julian
authors.initials: J
authors.lastname: Egger
authors.affiliation: Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
authors.forename: Abdijapar
authors.initials: A
authors.lastname: Shamshiev
authors.affiliation: Core Facility for Mass Spectrometry, Medical University of Graz, Graz, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Trötzmüller
authors.affiliation: Core Facility for Mass Spectrometry, Medical University of Graz, Graz, Austria.
authors.forename: Harald
authors.initials: H
authors.lastname: Köfeler
authors.affiliation: Laboratory of Organic Chemistry, Department of Chemistry, ETH Zurich, Zurich, Switzerland.
authors.forename: Erick M
authors.initials: EM
authors.lastname: Carreira
authors.affiliation: Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland manfred.kopf@ethz.ch stefan.freigang@pathology.unibe.ch.
authors.forename: Manfred
authors.initials: M
authors.lastname: Kopf
authors.affiliation: Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland manfred.kopf@ethz.ch stefan.freigang@pathology.unibe.ch.
authors.forename: Stefan
authors.initials: S
authors.lastname: Freigang
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000378:metabolism*; D003517:Cyclopentanes / Q000737:chemistry / Q000378:metabolism*; D015777:Eicosanoids / Q000737:chemistry / Q000378:metabolism*; D004852:Epoxy Compounds / Q000737:chemistry / Q000378:metabolism*; D008168:Lung / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010084:Oxidation-Reduction; D010742:Phospholipid Ethers / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology
chemical_list: C400184:1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphorylcholine; D000893:Anti-Inflammatory Agents; D003517:Cyclopentanes; D015777:Eicosanoids; D004852:Epoxy Compounds; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D010742:Phospholipid Ethers; C013905:cyclopentenone
keywords: Nrf2; inflammation; isoprostanes; lung injury; oxidized phospholipids