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<p>Atherosclerosis is the underlying cause of myocardial infarction and ischemic stroke. It is a lipid-triggered and cytokine/chemokine-driven arterial inflammatory condition. We identify D-dopachrome tautomerase/macrophage migration-inhibitory factor-2 (MIF-2), a paralog of the cytokine MIF, as an atypical chemokine promoting both atherosclerosis and hepatic lipid accumulation. In hyperlipidemic <i>Apoe</i><sup><i>–/–</i></sup> mice, <i>Mif-2</i>-deficiency and pharmacological MIF-2-blockade protect against lesion formation and vascular inflammation in early and advanced atherogenesis. MIF-2 promotes leukocyte migration, endothelial arrest, and foam-cell formation, and we identify CXCR4 as a receptor for MIF-2. <i>Mif-2-</i>deficiency <i>in Apoe</i><sup><i>–/–</i></sup> mice leads to decreased plasma lipid levels and suppressed hepatic lipid accumulation, characterized by reductions in lipogenesis-related pathways, tri-/diacylglycerides, and cholesterol-esters, as revealed by hepatic transcriptomics/lipidomics. Hepatocyte cultures and FLIM-FRET-microscopy suggest that MIF-2 activates SREBP-driven lipogenic genes, mechanistically involving MIF-2-inducible CD74/CXCR4 complexes and PI3K/AKT but not AMPK signaling. MIF-2 is upregulated in unstable carotid plaques from atherosclerotic patients and its plasma concentration correlates with disease severity in patients with coronary artery disease. These findings establish MIF-2 as an atypical chemokine linking vascular inflammation to metabolic dysfunction in atherosclerosis.</p>

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An atypical atherogenic chemokine that promotes advanced atherosclerosis and hepatic lipogenesis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月7日

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  • Omar El Bounkari,
  • Chunfang Zan,
  • Bishan Yang,
  • Simon Ebert,
  • Jonas Wagner,
  • Elina Bugar,
  • Naomi Kramer,
  • Priscila Bourilhon,
  • Christos Kontos,
  • Marlies Zarwel,
  • Dzmitry Sinitski,
  • Jelena Milic,
  • Yvonne Jansen,
  • Wolfgang E. Kempf,
  • Nadja Sachs,
  • Lars Maegdefessel,
  • Hao Ji,
  • Ozgun Gokce,
  • Fabien Riols,
  • Mark Haid,
  • Simona Gerra,
  • Adrian Hoffmann,
  • Markus Brandhofer,
  • Maida Avdic,
  • Richard Bucala,
  • Remco T. A. Megens,
  • Nienke Willemsen,
  • Denise Messerer,
  • Christian Schulz,
  • Alexander Bartelt,
  • Tobias Harm,
  • Dominik Rath,
  • Yvonne Döring,
  • Meinrad Gawaz,
  • Christian Weber,
  • Aphrodite Kapurniotu,
  • Jürgen Bernhagen

摘要

Atherosclerosis is the underlying cause of myocardial infarction and ischemic stroke. It is a lipid-triggered and cytokine/chemokine-driven arterial inflammatory condition. We identify D-dopachrome tautomerase/macrophage migration-inhibitory factor-2 (MIF-2), a paralog of the cytokine MIF, as an atypical chemokine promoting both atherosclerosis and hepatic lipid accumulation. In hyperlipidemic Apoe–/– mice, Mif-2-deficiency and pharmacological MIF-2-blockade protect against lesion formation and vascular inflammation in early and advanced atherogenesis. MIF-2 promotes leukocyte migration, endothelial arrest, and foam-cell formation, and we identify CXCR4 as a receptor for MIF-2. Mif-2-deficiency in Apoe–/– mice leads to decreased plasma lipid levels and suppressed hepatic lipid accumulation, characterized by reductions in lipogenesis-related pathways, tri-/diacylglycerides, and cholesterol-esters, as revealed by hepatic transcriptomics/lipidomics. Hepatocyte cultures and FLIM-FRET-microscopy suggest that MIF-2 activates SREBP-driven lipogenic genes, mechanistically involving MIF-2-inducible CD74/CXCR4 complexes and PI3K/AKT but not AMPK signaling. MIF-2 is upregulated in unstable carotid plaques from atherosclerotic patients and its plasma concentration correlates with disease severity in patients with coronary artery disease. These findings establish MIF-2 as an atypical chemokine linking vascular inflammation to metabolic dysfunction in atherosclerosis.