This is a summary of El Bounkari, O., Zan, C., Yang, B. et al. (2025). An atypical atherogenic chemokine that promotes advanced atherosclerosis and hepatic lipogenesis, published in Nature Communications: https://doi.org/10.1038/s41467-025-57540-z

The challenge

Atherosclerosis is the underlying condition responsible for both myocardial infarction and ischemic stroke; it is a chronic inflammatory disease of the arterial walls triggered by lipids and driven by immune and inflammatory pathways. For this study, we looked at the role of macrophage migration-inhibitory factor (MIF) proteins in atherosclerosis; MIF is a multifunctional inflammatory mediator implicated in various inflammatory diseases. Elevated plasma MIF levels are associated with coronary artery disease (CAD). Previous research, including our own, has shown increased MIF expression in atherosclerotic plaques and has demonstrated that MIF promotes the recruitment of atherogenic leukocytes through non-cognate interactions with chemokine receptors such as CXCR2 and CXCR4. Consequently, MIF is classified as an atypical chemokine, which is an emerging family of proteins that bind to classical chemokine receptors but lack typical chemokine structural features. While previous research has provided us with a reasonable understanding of the contribution of MIF, i.e. primarily driving vascular inflammation in atherosclerosis, the role of the MIF paralog MIF-2 (also termed D-dopachrome tautomerase, D-DT) in atherosclerosis had been unknown.

Our approach

We employed mouse models to study the role of MIF-2 in both early and advanced atherosclerosis. Specifically, we used Apolipoprotein E-deficient (Apoe^–/–) mice, either with a deficiency in Mif-2 or under pharmacological Mif-2 blockade, to examine the role of MIF-2 in the development of atherosclerosis. Additionally, we conducted mechanistic experiments that included transcriptomics, lipidomics, hepatocyte cultures, SREBP and target gene analysis, receptor blocking, proximity ligation assay (PLA), and FLIM/FRET techniques.

Our findings

We discovered that Mif-2^–/–Apoe^–/– mice on a high-fat diet had fewer atherosclerotic lesions, reduced vascular inflammation, and lower levels of circulating inflammatory cytokines in both early and advanced stages of atherogenesis compared to Apoe^–/– mice. We identified MIF-2 as a pro-atherogenic atypical chemokine and CXCR4 as its receptor. Unlike MIF, MIF-2 is also associated with lipid accumulation in the liver, and elevated levels of MIF-2 correlate with unstable carotid artery plaques and symptomatic coronary plaques. This suggests that MIF-2 plays a role in advanced atherosclerotic diseases, affecting both lipid/hepatic processes and vascular health.

The implications

These findings identify the protein MIF-2 as an atypical chemokine that links vascular inflammation to metabolic dysfunction in atherosclerosis. Our overall data suggest that MIF-2 could be a promising therapeutic target for atherosclerosis, vascular inflammation, and related metabolic conditions. Targeting MIF-2 may be most effective when combined with targeting MIF, as both MIF and MIF-2 are significant pro-atherogenic mediators that worsen vascular inflammation and lesion formation.

Creating SyNergies

The study was led by Jürgen Bernhagen, and Omar El Bounkari, a senior staff scientist in the BernhagenLab, and included SyNergy member Christian Weber. The project exemplies SyNergy efforts to comprehensively characterize interactions between cardio- and cerebro-vascular pathologies, inflammation, and metabolic diseases, including dyslipidemia, and will flank SyNergy’s aim to identify targets for translational approaches.