TY  - JOUR
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
TI  - An atypical atherogenic chemokine that promotes advanced atherosclerosis and hepatic lipogenesis.
JO  - Nature Communications
VL  - 16
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Springer Nature
M1  - DZNE-2025-00417
SP  - 2297
PY  - 2025
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
KW  - Atherosclerosis: pathology
KW  - Atherosclerosis: genetics
KW  - Humans
KW  - Mice
KW  - Liver: metabolism
KW  - Liver: pathology
KW  - Intramolecular Oxidoreductases: metabolism
KW  - Intramolecular Oxidoreductases: genetics
KW  - Male
KW  - Chemokines: metabolism
KW  - Receptors, CXCR4: metabolism
KW  - Receptors, CXCR4: genetics
KW  - Mice, Inbred C57BL
KW  - Hepatocytes: metabolism
KW  - Hepatocytes: pathology
KW  - Macrophage Migration-Inhibitory Factors: metabolism
KW  - Macrophage Migration-Inhibitory Factors: genetics
KW  - Mice, Knockout
KW  - Female
KW  - Signal Transduction
KW  - Foam Cells: metabolism
KW  - Intramolecular Oxidoreductases (NLM Chemicals)
KW  - Chemokines (NLM Chemicals)
KW  - Receptors, CXCR4 (NLM Chemicals)
KW  - dopachrome isomerase (NLM Chemicals)
KW  - Macrophage Migration-Inhibitory Factors (NLM Chemicals)
KW  - CXCR4 protein, mouse (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40055309
DO  - DOI:10.1038/s41467-025-57540-z
UR  - https://pub.dzne.de/record/277434
ER  -