RRC ID 32809
Author Bretscher P, Egger J, Shamshiev A, Trötzmüller M, Köfeler H, Carreira EM, Kopf M, Freigang S.
Title Phospholipid oxidation generates potent anti-inflammatory lipid mediators that mimic structurally related pro-resolving eicosanoids by activating Nrf2.
Journal EMBO Mol Med
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.
Volume 7(5)
Pages 593-607
Published 2015-5-1
DOI 10.15252/emmm.201404702
PII emmm.201404702
PMID 25770125
PMC PMC4492819
MeSH Animals Anti-Inflammatory Agents / chemistry Anti-Inflammatory Agents / metabolism* Cyclopentanes / chemistry Cyclopentanes / metabolism* Eicosanoids / chemistry Eicosanoids / metabolism* Epoxy Compounds / chemistry Epoxy Compounds / metabolism* Lung / pathology Mice, Inbred C57BL Mice, Knockout NF-E2-Related Factor 2 / metabolism* Oxidation-Reduction Phospholipid Ethers / metabolism* Th1 Cells / immunology
IF 8.821
Times Cited 45
Mice RBRC01390