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An atypical atherogenic chemokine that promotes advanced atherosclerosis and hepatic lipogenesis

Author

Listed:
  • 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)
    partner site Munich Heart Alliance)

  • Lars Maegdefessel

    (Technische Universität München (TUM)
    partner site Munich Heart Alliance)

  • Hao Ji

    (Ludwig Maximilian University (LMU) Munich)

  • Ozgun Gokce

    (Ludwig Maximilian University (LMU) Munich
    Munich Cluster for Systems Neurology (SyNergy)
    University Hospital Bonn Venusberg-Campus 1
    German Center for Neurodegenerative Diseases (DZNE) Bonn)

  • Fabien Riols

    (Helmholtz Zentrum)

  • Mark Haid

    (Helmholtz Zentrum)

  • Simona Gerra

    (Ludwig Maximilian University (LMU) Munich)

  • Adrian Hoffmann

    (Ludwig Maximilian University (LMU) Munich
    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
    partner site Munich Heart Alliance
    Maastricht University)

  • Nienke Willemsen

    (Ludwig Maximilian University (LMU) Munich)

  • Denise Messerer

    (Ludwig Maximilian University (LMU) Munich)

  • Christian Schulz

    (Ludwig Maximilian University (LMU) Munich
    University of Heidelberg)

  • Alexander Bartelt

    (Ludwig Maximilian University (LMU) Munich
    partner site Munich Heart Alliance
    German Research Center for Environmental Health)

  • Tobias Harm

    (Eberhard-Karls-University Tübingen)

  • Dominik Rath

    (Eberhard-Karls-University Tübingen)

  • Yvonne Döring

    (Ludwig Maximilian University (LMU) Munich
    University of Bern)

  • Meinrad Gawaz

    (Eberhard-Karls-University Tübingen)

  • Christian Weber

    (Ludwig Maximilian University (LMU) Munich
    partner site Munich Heart Alliance
    Munich Cluster for Systems Neurology (SyNergy)
    Maastricht University)

  • Aphrodite Kapurniotu

    (Technische Universität München (TUM))

  • Jürgen Bernhagen

    (Ludwig Maximilian University (LMU) Munich
    partner site Munich Heart Alliance
    Munich Cluster for Systems Neurology (SyNergy))

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.

Suggested Citation

  • 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 & Yvon, 2025. "An atypical atherogenic chemokine that promotes advanced atherosclerosis and hepatic lipogenesis," Nature Communications, Nature, vol. 16(1), pages 1-30, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57540-z
    DOI: 10.1038/s41467-025-57540-z
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    References listed on IDEAS

    as
    1. Christos Kontos & Omar El Bounkari & Christine Krammer & Dzmitry Sinitski & Kathleen Hille & Chunfang Zan & Guangyao Yan & Sijia Wang & Ying Gao & Markus Brandhofer & Remco T. A. Megens & Adrian Hoffm, 2020. "Designed CXCR4 mimic acts as a soluble chemokine receptor that blocks atherogenic inflammation by agonist-specific targeting," Nature Communications, Nature, vol. 11(1), pages 1-18, December.
    2. Runmin Wei & Jingye Wang & Erik Jia & Tianlu Chen & Yan Ni & Wei Jia, 2018. "GSimp: A Gibbs sampler based left-censored missing value imputation approach for metabolomics studies," PLOS Computational Biology, Public Library of Science, vol. 14(1), pages 1-14, January.
    3. Edward J. Miller & Ji Li & Lin Leng & Courtney McDonald & Toshiya Atsumi & Richard Bucala & Lawrence H. Young, 2008. "Macrophage migration inhibitory factor stimulates AMP-activated protein kinase in the ischaemic heart," Nature, Nature, vol. 451(7178), pages 578-582, January.
    4. Peter Libby & Paul M Ridker & Göran K. Hansson, 2011. "Progress and challenges in translating the biology of atherosclerosis," Nature, Nature, vol. 473(7347), pages 317-325, May.
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