An atypical atherogenic chemokine that promotes advanced atherosclerosis and hepatic lipogenesis

  • Nat Commun. 2025 Mar 7;16(1):2297. doi: 10.1038/s41467-025-57540-z.
Omar El Bounkari  #  1 ,  Chunfang Zan  #  2 ,  Bishan Yang  2 ,  Simon Ebert  2 ,  Jonas Wagner  2 ,  Elina Bugar  2 ,  Naomi Kramer  2 ,  Priscila Bourilhon  2 ,  Christos Kontos  3 ,  Marlies Zarwel  2 ,  Dzmitry Sinitski  2 ,  Jelena Milic  2 ,  Yvonne Jansen  4 ,  Wolfgang E Kempf  5 ,  Nadja Sachs  5  6 ,  Lars Maegdefessel  5  6 ,  Hao Ji  7 ,  Ozgun Gokce  7  8  9  10 ,  Fabien Riols  11 ,  Mark Haid  11 ,  Simona Gerra  2 ,  Adrian Hoffmann  2  12 ,  Markus Brandhofer  2 ,  Maida Avdic  2 ,  Richard Bucala  13 ,  Remco T A Megens  4  6  14 ,  Nienke Willemsen  4 ,  Denise Messerer  15 ,  Christian Schulz  15  16 ,  Alexander Bartelt  4  6  17 ,  Tobias Harm  18 ,  Dominik Rath  18 ,  Yvonne Döring  4  19 ,  Meinrad Gawaz  18 ,  Christian Weber  4  6  8  14 ,  Aphrodite Kapurniotu  3 ,  Jürgen Bernhagen  20  21  22
Affiliations
  • 1. Division of Vascular Biology, Institute for Stroke and Dementia Research (ISD), LMU Klinikum, Ludwig Maximilian University (LMU) Munich, Munich, Germany. [email protected].
  • 2. Division of Vascular Biology, Institute for Stroke and Dementia Research (ISD), LMU Klinikum, Ludwig Maximilian University (LMU) Munich, Munich, Germany.
  • 3. Division of Peptide Biochemistry, TUM School of Life Sciences, Technische Universität München (TUM), Freising, Germany.
  • 4. Institute for Cardiovascular Prevention, LMU Klinikum, Ludwig Maximilian University (LMU) Munich, Munich, Germany.
  • 5. Institute of Molecular Vascular Medicine, TUM Klinikum, Technische Universität München (TUM), Munich, Germany.
  • 6. German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany.
  • 7. Systems Neuroscience Lab, Institute for Stroke and Dementia Research (ISD), LMU Klinikum, Ludwig Maximilian University (LMU) Munich, Munich, Germany.
  • 8. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
  • 9. Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn Venusberg-Campus 1, Bonn, Germany.
  • 10. German Center for Neurodegenerative Diseases (DZNE) Bonn, Munich, Germany.
  • 11. Metabolomics and Proteomics Core, Helmholtz Zentrum, Neuherberg, Germany.
  • 12. Department of Anaesthesiology, LMU Klinikum, Ludwig Maximilian University (LMU) Munich, Munich, Germany.
  • 13. Yale University School of Medicine, New Haven, CT, USA.
  • 14. Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands.
  • 15. Department of Medicine I, LMU Klinikum, Ludwig Maximilian University (LMU) Munich, Munich, Germany.
  • 16. Department of Immunopharmacology, Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
  • 17. Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany.
  • 18. Department of Cardiology and Angiology, University Hospital Tübingen, Eberhard-Karls-University Tübingen, Tübingen, Germany.
  • 19. Division of Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
  • 20. Division of Vascular Biology, Institute for Stroke and Dementia Research (ISD), LMU Klinikum, Ludwig Maximilian University (LMU) Munich, Munich, Germany. [email protected].
  • 21. German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany. [email protected].
  • 22. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. [email protected].
  • # Contributed equally.
PMID: 40055309 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.

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