An atypical atherogenic chemokine that promotes advanced atherosclerosis and hepatic lipogenesis

El Bounkari, Omar ; Zan, Chunfang; Yang, Bishan; Ebert, Simon ; Wagner, Jonas; Bugar, Elina; Kramer, Naomi; Bourilhon, Priscila; Kontos, Christos; Zarwel, Marlies; Sinitski, Dzmitry; Milic, Jelena; Jansen, Yvonne; Kempf, Wolfgang E.; Sachs, Nadja ; Maegdefessel, Lars ; Ji, Hao; Gokce, Ozgun ; Riols, Fabien; Haid, Mark ; Gerra, Simona; Hoffmann, Adrian ; Brandhofer, Markus ; Avdic, Maida; Bucala, Richard; Megens, Remco T. A. ; Willemsen, Nienke; Messerer, Denise; Schulz, Christian ; Bartelt, Alexander ; Harm, Tobias; Rath, Dominik; Döring, Yvonne ; Gawaz, Meinrad ; Weber, Christian ; Kapurniotu, Aphrodite und Bernhagen, Jürgen (2025): An atypical atherogenic chemokine that promotes advanced atherosclerosis and hepatic lipogenesis. In: Nature Communications, Bd. 16, 2297

Abstract

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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Munich Cluster for Systems Neurology (SyNergy) ; Medizin > Institut für Schlaganfall- und Demenzforschung (ISD) ; Medizin > Klinikum der LMU München ; Medizin > Klinikum der LMU München > Klinik für Anaesthesiologie ; Medizin > Klinikum der LMU München > Medizinische Klinik und Poliklinik I (Kardiologie)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 2041-1723
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198