Bretscher, Peter; Egger, Julian; Shamshiev, Abdijapar; Trötzmüller, Martin; Köfeler, Harald; Carreira, Erick M; Kopf, Manfred; Freigang, Stefan Bernd (2015). Phospholipid oxidation generates potent anti-inflammatory lipid mediators that mimic structurally related pro-resolving eicosanoids by activating Nrf2. EMBO molecular medicine, 7(5), pp. 593-607. EMBO Press 10.15252/emmm.201404702
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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.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
04 Faculty of Medicine > Service Sector > Institute of Pathology 04 Faculty of Medicine > Service Sector > Institute of Pathology > Immunopathology |
UniBE Contributor: |
Freigang, Stefan Bernd |
Subjects: |
500 Science > 570 Life sciences; biology 600 Technology > 610 Medicine & health |
ISSN: |
1757-4684 |
Publisher: |
EMBO Press |
Language: |
English |
Submitter: |
Doris Haefelin |
Date Deposited: |
13 Jul 2015 15:21 |
Last Modified: |
05 Dec 2022 14:48 |
Publisher DOI: |
10.15252/emmm.201404702 |
PubMed ID: |
25770125 |
Uncontrolled Keywords: |
Nrf2; inflammation; isoprostanes; lung injury; oxidized phospholipids |
BORIS DOI: |
10.7892/boris.70217 |
URI: |
https://boris.unibe.ch/id/eprint/70217 |