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; Bernhagen, Jürgen (2025): An atypical atherogenic chemokine that promotes advanced atherosclerosis and hepatic lipogenesis. Nature Communications, 16: 2297. ISSN 2041-1723

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.

• Doc-Type: Article (LMU Hospital)
• Organisational unit (Faculties): 07 Medicine > Medical Center of the University of Munich > Institute for Stroke and Dementia Research (ISD)
• DFG subject classification of scientific disciplines: Life sciences
• DFG: Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - 238187445
• DFG: Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - 491502892