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 (Ox PL ) species, which contribute to the development of chronic inflammatory diseases and metabolic disorders. While the ability of Ox PL to modulate biological processes is increasingly recognized, the nature of the biologically active Ox PL 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 Ox PL 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 Ox PL variants, we identified a synthetic Ox PL 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. image This study characterizes the potent anti‐inflammatory bioactivity of oxidized phospholipids and identifies a fatty acid epoxycyclopentenone as the active component that triggers Nrf2 signaling in myeloid cells and alleviates inflammation and endotoxin‐induced lung injury in a mouse model. Epoxycyclopentenone‐containing phospholipids broadly inhibit pro‐inflammatory cytokine and chemokine responses of myeloid cells and prevent the development of inflammatory Th1 cells. Epoxycyclopentenone and endogenous pro‐resolving lipid mediators sharing the cyclopentenone motif activate the oxidative stress‐responsive transcription factor Nrf2 to dampen inflammation in vitro and in vivo . Administration of epoxycyclopentenone activates Nrf2 signaling in vivo and mitigates endotoxin‐induced lung injury in the mouse model. Structure–function studies identified critical molecular determinants of this anti‐inflammatory bioactivity and facilitated the development of an epoxycyclopentenone‐derived lipid variant with greatly increased potency.