An atypical atherogenic chemokine that promotes advanced athero¬sclerosis and hepatic lipogenesis

Atherosclerosis is the underlying cause of myocardial infarction and ischemic stroke. It is a lipid-triggered inflammatory condition of arterial vessels driven by cytokines and chemokines. Chemokines that affect both vascular and metabolic pathologies are rare. Here we show that D-dopachrome tautomerase (D-DT)/macrophage migration inhibitory factor-2 (MIF-2), a paralog of the atherogenic cytokine MIF, is a novel atypical chemokine promoting athero-sclerotic plaque formation and hepatic lipid accumulation. Mif-2 deficiency and its pharma-cological blockade in hyperlipidemic atherogenic Apoe-/- mice protected against lesion formation and vascular inflammation in early and advanced atherogenesis. MIF-2 promoted monocyte migration and arrest on aortic endothelial monolayers, promoted B-cell recruitment, and increased foam cell formation. Employing biochemical and cellular assays, we identified CXCR4 as a novel receptor for MIF-2. Notably, Mif-2-/-Apoe-/- mice exhibited decreased plasma lipid levels, smaller livers, and reduced hepatic lipid accumulation compared to Apoe-/- mice. Comparison of the hepatic transcriptome and lipidome between Apoe-/- and Mif-2-/-Apoe-/- mice revealed a notable enrichment of lipogenesis-related pathways, triacylglycerides, diacylglycerides, and cholesterol esters in Mif-2-proficient mice. Mechanistic experiments in hepatocytes suggested that MIF-2 regulates activation of SREBP transcription factors to induce down¬stream lipogenic genes, while upstream, this pathway was mediated by the receptors CD74 and CXCR4, and PI3K/AKT but not AMPK signaling. Proximity ligation and FLIM-FRET multiphoton-microscopy indicated that CXCR4 and CD74 form a MIF-2-inducible heteromeric complex. Lastly, MIF-2 was found upregulated in unstable human carotid plaques from atherosclerotic patients undergoing carotid endarterectomy (CEA), suggesting a role for MIF-2 in advanced stages of athero¬sclerosis. Moreover, plasma concentrations of MIF-2 were increased in patients with coronary artery disease (CAD) and correlated with disease severity. Together, these data identify MIF-2 as a novel atherogenic chemokine and CXCR4 ligand associated with CAD that not only promotes lesion formation and vascular inflammation, but also affects hepatic lipogenesis in a CD74/CXCR4/SREBP-mediated manner. MIF-2 may thus be a novel player in atherosclerotic and metabolic disease.