%0 Journal Article
%A El Bounkari, Omar
%A Zan, Chunfang
%A Yang, Bishan
%A Ebert, Simon
%A Wagner, Jonas
%A Bugar, Elina
%A Kramer, Naomi
%A Bourilhon, Priscila
%A Kontos, Christos
%A Zarwel, Marlies
%A Sinitski, Dzmitry
%A Milic, Jelena
%A Jansen, Yvonne
%A Kempf, Wolfgang E
%A Sachs, Nadja
%A Maegdefessel, Lars
%A Ji, Hao
%A Gokce, Ozgun
%A Riols, Fabien
%A Haid, Mark
%A Gerra, Simona
%A Hoffmann, Adrian
%A Brandhofer, Markus
%A Avdic, Maida
%A Bucala, Richard
%A Megens, Remco T A
%A Willemsen, Nienke
%A Messerer, Denise
%A Schulz, Christian
%A Bartelt, Alexander
%A Harm, Tobias
%A Rath, Dominik
%A Döring, Yvonne
%A Gawaz, Meinrad
%A Weber, Christian
%A Kapurniotu, Aphrodite
%A Bernhagen, Jürgen
%T An atypical atherogenic chemokine that promotes advanced atherosclerosis and hepatic lipogenesis.
%J Nature Communications
%V 16
%N 1
%@ 2041-1723
%C [London]
%I Springer Nature
%M DZNE-2025-00417
%P 2297
%D 2025
%X 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.
%K Animals
%K Lipogenesis: genetics
%K Atherosclerosis: metabolism
%K Atherosclerosis: pathology
%K Atherosclerosis: genetics
%K Humans
%K Mice
%K Liver: metabolism
%K Liver: pathology
%K Intramolecular Oxidoreductases: metabolism
%K Intramolecular Oxidoreductases: genetics
%K Male
%K Chemokines: metabolism
%K Receptors, CXCR4: metabolism
%K Receptors, CXCR4: genetics
%K Mice, Inbred C57BL
%K Hepatocytes: metabolism
%K Hepatocytes: pathology
%K Macrophage Migration-Inhibitory Factors: metabolism
%K Macrophage Migration-Inhibitory Factors: genetics
%K Mice, Knockout
%K Female
%K Signal Transduction
%K Foam Cells: metabolism
%K Intramolecular Oxidoreductases (NLM Chemicals)
%K Chemokines (NLM Chemicals)
%K Receptors, CXCR4 (NLM Chemicals)
%K dopachrome isomerase (NLM Chemicals)
%K Macrophage Migration-Inhibitory Factors (NLM Chemicals)
%K CXCR4 protein, mouse (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40055309
%R 10.1038/s41467-025-57540-z
%U https://pub.dzne.de/record/277434