An atypical atherogenic chemokine that promotes advanced atherosclerosis and hepatic lipogenesis
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 aty...
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| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
07 March 2025
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| In: |
Nature Communications
Year: 2025, Jahrgang: 16, Pages: 1-30 |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-025-57540-z |
| Online-Zugang: | Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41467-025-57540-z Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41467-025-57540-z 
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| Verfasserangaben: | 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 |
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| 520 | |a 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. | ||
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