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El Bounkari, O.* ; Zan, C.* ; Yang, B.* ; Ebert, S.* ; Wagner, J.* ; Bugar, E.* ; Krämer, N.* ; Bourilhon, P.* ; Kontos, C.* ; Zarwel, M.* ; Sinitski, D.* ; Milic, J.* ; Jansen, Y.* ; Kempf, W.E.* ; Sachs, N.* ; Maegdefessel, L.* ; Ji, H.* ; Gokce, O.* ; 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.*

An atypical atherogenic chemokine that promotes advanced atherosclerosis and hepatic lipogenesis.

Nat. Commun. 16:2297 (2025)

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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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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Migration Inhibitory Factor; D-dopachrome Tautomerase; Element-binding Protein-1; Insulin-resistance; Receptors Cxcr4; Srebp Activity; D-dt; Mif; Expression; Cytokine

ISSN (print) / ISBN 2041-1723

e-ISSN 2041-1723

Journal Nature Communications

Quellenangaben Volume: 16, Issue: 1, Article Number: 2297

Publisher Nature Publishing Group

Publishing Place London

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) CF Metabolomics & Proteomics (CF-MPC)
Institute of Diabetes and Cancer (IDC)

Grants China Scholarship Council (CSC) fellowship program CSC/LMU
DFG under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology
German Center for Cardiovascular Research (DZHK) Junior Research Group Grant
Clinician Scientist Program of the German Cardiac Society (DGK)
US NIH
Deutsche Forschungsgemeinschaft (DFG)