Plasmalogen remodeling modulates macrophage response to cytotoxic oxysterols and atherosclerotic plaque vulnerability.

Fiche publication

Date publication

mai 2025

Journal

Cell reports. Medicine

Auteurs

Membres identifiés du Cancéropôle Est :
Dr HERMETET François , Dr LAGROST Laurent , Dr PAIS DE BARROS Jean-Paul , Pr MASSON David , Dr AIRES Virginie , Pr LESNIEWSKA Eric

Tous les auteurs :
Jalil A, Pilot T, Bourgeois T, Laubriet A, Li X, Diedisheim M, Deckert V, Magnani C, Le Guern N, Pais de Barros JP, Nguyen M, Pallot G, Vouilloz A, Proukhnitzky L, Hermetet F, Aires V, Lesniewska E, Lagrost L, Auwerx J, Le Goff W, Venteclef N, Steinmetz E, Thomas C, Masson D

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/40345182

Résumé

Essential fatty acid metabolism in myeloid cells plays a critical but underexplored role in immune function. Here, we demonstrate that simultaneous inactivation of two key enzymes involved in macrophage polyunsaturated fatty acid (PUFA) metabolism-ELOVL5, which elongates long-chain PUFAs, and LPCAT3, which incorporates them into phospholipids-disrupts membrane organization by promoting the formation of cholesterol-enriched domains. This increases macrophage sensitivity to cytotoxic oxysterols and leads to more vulnerable atherosclerotic plaques with enlarged necrotic cores in a mouse model of atherosclerosis. In humans, analysis of 187 carotid plaques reveals a positive correlation between LPCAT3/ELOVL5-generated phospholipids-including arachidonate (C20:4 n-6)-containing ether lipids-and more stable plaque profiles. Additionally, Mendelian randomization analysis supports a causal relationship between LPCAT3 expression and reduced risk of ischemic stroke. Our findings uncover a regulatory circuit essential for PUFA-containing phospholipid generation in macrophages, positioning PUFA-containing ether lipids as promising biomarkers and therapeutic targets.