Journal Article

DZNE-2025-00417

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png An atypical atherogenic chemokine that promotes advanced atherosclerosis and hepatic lipogenesis.

El Bounkari, O. ; Zan, C. ; Yang, B. ; Ebert, S.Extern* ; Wagner, J. ; Bugar, E. ; Kramer, N. ; Bourilhon, P. ; Kontos, C. ; Zarwel, M. ; Sinitski, D. ; Milic, J. ; Jansen, Y. ; Kempf, W. E. ; Sachs, N. ; Maegdefessel, L. ; Ji, H. ; Gokce, O.DZNE* ; Riols, F. ; Haid, M. ; Gerra, S. ; Hoffmann, A. ; Brandhofer, M. ; Avdic, M. ; Bucala, R. ; Megens, R. T. A. ; Willemsen, N. ; Messerer, D. ; Schulz, C. ; Bartelt, A. ; Harm, T. ; Rath, D. ; Döring, Y. ; Gawaz, M. ; Weber, C. ; Kapurniotu, A. ; Bernhagen, J.

2025
Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41467-025-57540-z

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.

Keyword(s): Animals (MeSH) ; Lipogenesis: genetics (MeSH) ; Atherosclerosis: metabolism (MeSH) ; Atherosclerosis: pathology (MeSH) ; Atherosclerosis: genetics (MeSH) ; Humans (MeSH) ; Mice (MeSH) ; Liver: metabolism (MeSH) ; Liver: pathology (MeSH) ; Intramolecular Oxidoreductases: metabolism (MeSH) ; Intramolecular Oxidoreductases: genetics (MeSH) ; Male (MeSH) ; Chemokines: metabolism (MeSH) ; Receptors, CXCR4: metabolism (MeSH) ; Receptors, CXCR4: genetics (MeSH) ; Mice, Inbred C57BL (MeSH) ; Hepatocytes: metabolism (MeSH) ; Hepatocytes: pathology (MeSH) ; Macrophage Migration-Inhibitory Factors: metabolism (MeSH) ; Macrophage Migration-Inhibitory Factors: genetics (MeSH) ; Mice, Knockout (MeSH) ; Female (MeSH) ; Signal Transduction (MeSH) ; Foam Cells: metabolism (MeSH) ; Intramolecular Oxidoreductases ; Chemokines ; Receptors, CXCR4 ; dopachrome isomerase ; Macrophage Migration-Inhibitory Factors ; CXCR4 protein, mouse

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Contributing Institute(s):

1. Spatial Dynamics of Neurodegeneration (AG Gokce)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)

Appears in the scientific report 2025

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