An atypical atherogenic chemokine that promotes advanced atherosclerosis and hepatic lipogenesis
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<sup>-/-</sup> 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<sup>-/-</sup> 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.
Authors
- W. Kempf (ORCID: https://orcid.org/0000-0002-3960-5897)
- Simon Ebert (ORCID: https://orcid.org/0009-0004-5776-2089)
- Alexander Bartelt (ORCID: https://orcid.org/0000-0001-7840-3991)
- Nadja Sachs (ORCID: https://orcid.org/0000-0001-8031-017X)
- Naomi E. Kramer (ORCID: https://orcid.org/0000-0002-8208-7992)
- Richard Bucala (ORCID: https://orcid.org/0000-0001-5783-5736)
- Dzmitry Sinitski
- Aphrodite Kapurniotu (ORCID: https://orcid.org/0000-0001-6124-7232)
- Lars Mäegdefessel (ORCID: https://orcid.org/0000-0001-5228-2634)
- Simona Gerra (ORCID: https://orcid.org/0009-0005-6061-5124)
- Jonas Wagner (ORCID: https://orcid.org/0000-0001-5136-9922)
- Christos K. Kontos (ORCID: https://orcid.org/0000-0002-9935-8461)
- Priscila Bourilhon (ORCID: https://orcid.org/0000-0002-0693-4467)
- Hao Ji (ORCID: https://orcid.org/0000-0003-2371-6098)
- Marlies Zarwel
- Omar El Bounkari (ORCID: https://orcid.org/0000-0002-3051-2096)
- Markus Brandhofer (ORCID: https://orcid.org/0000-0002-1629-8353)
- Jelena Milić (ORCID: https://orcid.org/0000-0002-3596-5908)
- Remco T. A. Megens (ORCID: https://orcid.org/0000-0001-9871-6696)
- Dominik Rath (ORCID: https://orcid.org/0000-0002-5008-2572)
- Denise Messerer
- Nienke Willemsen (ORCID: https://orcid.org/0000-0003-1571-4236)
- Yvonne Jansen (ORCID: https://orcid.org/0000-0002-1283-8260)
- Yvonne Döring (ORCID: https://orcid.org/0000-0001-9307-3396)
- Elina Bugar
- Chunfang Zan
- Adrian Hoffmann (ORCID: https://orcid.org/0009-0000-0661-2321)
- Mark Haid (ORCID: https://orcid.org/0000-0001-6118-1333)
- Tobias Harm (ORCID: https://orcid.org/0000-0002-6121-2694)
- Meinrad Gawaz (ORCID: https://orcid.org/0000-0003-1124-9592)
- Jürgen Bernhagen (ORCID: https://orcid.org/0000-0003-2996-2652)
- Fabien Riols
- Özgün Gökçe (ORCID: https://orcid.org/0000-0001-6319-404X)
- Christian Weber (ORCID: https://orcid.org/0000-0003-4610-8714)
- Bishan Yang
- Christian Schulz (ORCID: https://orcid.org/0000-0002-8149-0747)
- Maida Avdic
Institutions
- University of Bern (CH)
- University of Mannheim (DE)
- Heidelberg University (DE)
- University Hospital Bonn (DE)
- University Hospital of Bern (CH)
- German Center for Neurodegenerative Diseases (DE)
- University Hospital Heidelberg (DE)
- Helmholtz Zentrum München (DE)
- LMU Klinikum (DE)
- Yale University (US)
- Maastricht University (NL)
- Munich Cluster for Systems Neurology (DE)
- University Children's Hospital Tübingen (DE)
- German Centre for Cardiovascular Research (DE)
- University Medical Centre Mannheim (DE)
- German Center for Diabetes Research (DE)
- Technical University of Munich (DE)
- University of Tübingen (DE)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-07
- DOI
- https://doi.org/10.1038/s41467-025-57540-z
- Citations
- 12
- Primary Topic
- Macrophage Migration Inhibitory Factor
- Type
- article
- Field-Weighted Citation Impact
- 9.57
Funders
- Deutsches Zentrum für Herz-Kreislaufforschung
- Deutsche Forschungsgemeinschaft
- China Scholarship Council
- Deutsche Gesellschaft für Kardiologie-Herz und Kreislaufforschung.
- National Institutes of Health