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; Jürgen Bernhagen

doi:10.1038/s41467-025-57540-z

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 HaidSimona 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, Jürgen Bernhagen^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Article number	2297
Number of pages	30
Journal	Nature Communications
Volume	16
Issue number	1
DOIs	https://doi.org/10.1038/s41467-025-57540-z
Publication status	Published - 7 Mar 2025

Keywords

Animals
Lipogenesis/genetics
Atherosclerosis/metabolism pathology genetics
Humans
Mice
Liver/metabolism pathology
Intramolecular Oxidoreductases/metabolism genetics
Male
Chemokines/metabolism
Receptors, CXCR4/metabolism genetics
Mice, Inbred C57BL
Hepatocytes/metabolism pathology
Macrophage Migration-Inhibitory Factors/metabolism genetics
Mice, Knockout
Female
Signal Transduction
Foam Cells/metabolism

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El Bounkari, O., Zan, C., Yang, B., Ebert, S., Wagner, J., Bugar, E., Kramer, 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., ... Bernhagen, J. (2025). An atypical atherogenic chemokine that promotes advanced atherosclerosis and hepatic lipogenesis. Nature Communications, 16(1), Article 2297. https://doi.org/10.1038/s41467-025-57540-z

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title = "An atypical atherogenic chemokine that promotes advanced atherosclerosis and hepatic lipogenesis",

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.",

keywords = "Animals, Lipogenesis/genetics, Atherosclerosis/metabolism pathology genetics, Humans, Mice, Liver/metabolism pathology, Intramolecular Oxidoreductases/metabolism genetics, Male, Chemokines/metabolism, Receptors, CXCR4/metabolism genetics, Mice, Inbred C57BL, Hepatocytes/metabolism pathology, Macrophage Migration-Inhibitory Factors/metabolism genetics, Mice, Knockout, Female, Signal Transduction, Foam Cells/metabolism",

author = "{El Bounkari}, Omar and Chunfang Zan and Bishan Yang and Simon Ebert and Jonas Wagner and Elina Bugar and Naomi Kramer and Priscila Bourilhon and Christos Kontos and Marlies Zarwel and Dzmitry Sinitski and Jelena Milic and Yvonne Jansen and Kempf, {Wolfgang E} and Nadja Sachs and Lars Maegdefessel and Hao Ji and Ozgun Gokce and Fabien Riols and Mark Haid and Simona Gerra and Adrian Hoffmann and Markus Brandhofer and Maida Avdic and Richard Bucala and Megens, {Remco T A} and Nienke Willemsen and Denise Messerer and Christian Schulz and Alexander Bartelt and Tobias Harm and Dominik Rath and Yvonne D{\"o}ring and Meinrad Gawaz and Christian Weber and Aphrodite Kapurniotu and J{\"u}rgen Bernhagen",

year = "2025",

month = mar,

day = "7",

doi = "10.1038/s41467-025-57540-z",

language = "English",

volume = "16",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

El Bounkari, O, Zan, C, Yang, B, Ebert, S, Wagner, J, Bugar, E, Kramer, N, Bourilhon, P, Kontos, C, Zarwel, M, Sinitski, D, Milic, J, Jansen, Y, Kempf, WE, Sachs, N, Maegdefessel, L, Ji, H, Gokce, O, Riols, F, Haid, M, Gerra, S, Hoffmann, A, Brandhofer, M, Avdic, M, Bucala, R, Megens, RTA, Willemsen, N, Messerer, D, Schulz, C, Bartelt, A, Harm, T, Rath, D, Döring, Y, Gawaz, M, Weber, C, Kapurniotu, A & Bernhagen, J 2025, 'An atypical atherogenic chemokine that promotes advanced atherosclerosis and hepatic lipogenesis', Nature Communications, vol. 16, no. 1, 2297. https://doi.org/10.1038/s41467-025-57540-z

TY - JOUR

T1 - An atypical atherogenic chemokine that promotes advanced atherosclerosis and hepatic lipogenesis

AU - El Bounkari, Omar

AU - Zan, Chunfang

AU - Yang, Bishan

AU - Ebert, Simon

AU - Wagner, Jonas

AU - Bugar, Elina

AU - Kramer, Naomi

AU - Bourilhon, Priscila

AU - Kontos, Christos

AU - Zarwel, Marlies

AU - Sinitski, Dzmitry

AU - Milic, Jelena

AU - Jansen, Yvonne

AU - Kempf, Wolfgang E

AU - Sachs, Nadja

AU - Maegdefessel, Lars

AU - Ji, Hao

AU - Gokce, Ozgun

AU - Riols, Fabien

AU - Haid, Mark

AU - Gerra, Simona

AU - Hoffmann, Adrian

AU - Brandhofer, Markus

AU - Avdic, Maida

AU - Bucala, Richard

AU - Megens, Remco T A

AU - Willemsen, Nienke

AU - Messerer, Denise

AU - Schulz, Christian

AU - Bartelt, Alexander

AU - Harm, Tobias

AU - Rath, Dominik

AU - Döring, Yvonne

AU - Gawaz, Meinrad

AU - Weber, Christian

AU - Kapurniotu, Aphrodite

AU - Bernhagen, Jürgen

PY - 2025/3/7

Y1 - 2025/3/7

N2 - 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.

AB - 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.

KW - Animals

KW - Lipogenesis/genetics

KW - Atherosclerosis/metabolism pathology genetics

KW - Humans

KW - Mice

KW - Liver/metabolism pathology

KW - Intramolecular Oxidoreductases/metabolism genetics

KW - Male

KW - Chemokines/metabolism

KW - Receptors, CXCR4/metabolism genetics

KW - Mice, Inbred C57BL

KW - Hepatocytes/metabolism pathology

KW - Macrophage Migration-Inhibitory Factors/metabolism genetics

KW - Mice, Knockout

KW - Female

KW - Signal Transduction

KW - Foam Cells/metabolism

U2 - 10.1038/s41467-025-57540-z

DO - 10.1038/s41467-025-57540-z

M3 - Article

SN - 2041-1723

VL - 16

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2297

ER -

An atypical atherogenic chemokine that promotes advanced atherosclerosis and hepatic lipogenesis

Abstract

Keywords

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