An atypical atherogenic chemokine that promotes advanced atherosclerosis and hepatic lipogenesis

Omar El Bounkari (), Chunfang Zan, Bishan Yang, Simon Ebert, Jonas Wagner, Elina Bugar, Naomi Kramer, Priscila Bourilhon, Christos Kontos, Marlies Zarwel, Dzmitry Sinitski, Jelena Milic, Yvonne Jansen, Wolfgang E. Kempf, Nadja Sachs, Lars Maegdefessel, Hao Ji, Ozgun Gokce, Fabien Riols, Mark Haid, Simona Gerra, Adrian Hoffmann, Markus Brandhofer, Maida Avdic, Richard Bucala, Remco T. A. Megens, Nienke Willemsen, Denise Messerer, Christian Schulz, Alexander Bartelt, Tobias Harm, Dominik Rath, Yvonne Döring, Meinrad Gawaz, Christian Weber, Aphrodite Kapurniotu and Jürgen Bernhagen ()
Additional contact information
Omar El Bounkari: Ludwig Maximilian University (LMU) Munich
Chunfang Zan: Ludwig Maximilian University (LMU) Munich
Bishan Yang: Ludwig Maximilian University (LMU) Munich
Simon Ebert: Ludwig Maximilian University (LMU) Munich
Jonas Wagner: Ludwig Maximilian University (LMU) Munich
Elina Bugar: Ludwig Maximilian University (LMU) Munich
Naomi Kramer: Ludwig Maximilian University (LMU) Munich
Priscila Bourilhon: Ludwig Maximilian University (LMU) Munich
Christos Kontos: Technische Universität München (TUM)
Marlies Zarwel: Ludwig Maximilian University (LMU) Munich
Dzmitry Sinitski: Ludwig Maximilian University (LMU) Munich
Jelena Milic: Ludwig Maximilian University (LMU) Munich
Yvonne Jansen: Ludwig Maximilian University (LMU) Munich
Wolfgang E. Kempf: Technische Universität München (TUM)
Nadja Sachs: Technische Universität München (TUM)
Lars Maegdefessel: Technische Universität München (TUM)
Hao Ji: Ludwig Maximilian University (LMU) Munich
Ozgun Gokce: Ludwig Maximilian University (LMU) Munich
Fabien Riols: Helmholtz Zentrum
Mark Haid: Helmholtz Zentrum
Simona Gerra: Ludwig Maximilian University (LMU) Munich
Adrian Hoffmann: Ludwig Maximilian University (LMU) Munich
Markus Brandhofer: Ludwig Maximilian University (LMU) Munich
Maida Avdic: Ludwig Maximilian University (LMU) Munich
Richard Bucala: Yale University School of Medicine
Remco T. A. Megens: Ludwig Maximilian University (LMU) Munich
Nienke Willemsen: Ludwig Maximilian University (LMU) Munich
Denise Messerer: Ludwig Maximilian University (LMU) Munich
Christian Schulz: Ludwig Maximilian University (LMU) Munich
Alexander Bartelt: Ludwig Maximilian University (LMU) Munich
Tobias Harm: Eberhard-Karls-University Tübingen
Dominik Rath: Eberhard-Karls-University Tübingen
Yvonne Döring: Ludwig Maximilian University (LMU) Munich
Meinrad Gawaz: Eberhard-Karls-University Tübingen
Christian Weber: Ludwig Maximilian University (LMU) Munich
Aphrodite Kapurniotu: Technische Universität München (TUM)
Jürgen Bernhagen: Ludwig Maximilian University (LMU) Munich

Nature Communications, 2025, vol. 16, issue 1, 1-30

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57540-z

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