Article Dans Une Revue Cell Reports Medicine Année : 2025

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

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.

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hal-05445841 , version 1 (07-01-2026)

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Antoine Jalil, Thomas Pilot, Thibaut Bourgeois, Aline Laubriet, Xiaoxu Li, et al.. Plasmalogen remodeling modulates macrophage response to cytotoxic oxysterols and atherosclerotic plaque vulnerability. Cell Reports Medicine, 2025, 6 (5), pp.102131. ⟨10.1016/j.xcrm.2025.102131⟩. ⟨hal-05445841⟩
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