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.
Highlights
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
Exposure of bone marrow-derived dendritic cells (BMDC) to oxidized PAPC (OxPAPC) strongly inhibited their subsequent ability to produce the pro-inflammatory cytokines interleukin (IL)-6 and IL-12 in response to stimulation of the Toll-like receptor (TLR) 7 with imiquimod (Fig 1A). This potent anti-inflammatory bioactivity of OxPAPC could be directly attributed to the oxidative modification of PAPC, since treatment with 1,2-di-palmitoyl-sn-glycero-3-phosphocholine (DPPC), a phospholipid with no unsaturated acyl chains that is inert to oxidation, did not show such effect (Fig 1A)
We have characterized the potent anti-inflammatory activity of OxPAPC in vitro and in vivo and identified a distinct molecular OxPL species that mediates these effects by signaling via the oxidative stress-responsive transcription factor nuclear factor E2-related factor 2 (Nrf2)
Summary
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. 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
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