Phospholipid oxidation generates potent anti-inflammatory lipid mediators that mimic structurally related pro-resolving eicosanoids by activating Nrf2.

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)

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:

01 Feb 2017 14:10

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

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