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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 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE281285 | GEO | 2025/03/13

REPOSITORIES: GEO

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Project description: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.

Project description:Atherosclerosis is a chronic inflammatory condition of our arteries and the main underlying pathology of myocardial infarction and stroke. The pathogenesis is age-dependent, but the links between disease progression, age, and atherogenic cytokines and chemokines are incompletely understood. Here, we studied the chemokine-like inflammatory cytokine macrophage migration inhibitory factor (MIF) in atherogenic Apoe–/– mice across different stages of aging and cholesterol-rich high-fat diet (HFD). MIF promotes atherosclerosis by mediating leukocyte recruitment, lesional inflammation, and suppressing atheroprotective B- cells. However, links between MIF and advanced atherosclerosis across aging have not been systematically explored. We compared effects of global Mif-gene deficiency in 30-, 42-, and 48-week-old Apoe–/– mice on HFD for 24, 36, or 42 weeks, respectively, and in 52-week- old mice on a 6-week HFD. Mif-deficient mice exhibited reduced atherosclerotic lesions in the 30/24- and 42/36-week-old groups, but atheroprotection, which in the applied Apoe–/– model was limited to lesions in the brachiocephalic artery and abdominal aorta, was not detected in the 48/42- and 52/6-week-old groups. This suggested that atheroprotection afforded by global Mif-gene deletion differs across aging stages and atherogenic diet duration. To characterize this phenotype and study the underlying mechanisms, we determined immune cells in the periphery and vascular lesions, obtained a multiplex cytokine/chemokine profile, and compared the transcriptome between the age-related phenotypes. We found that Mif- deficiency promotes lesional macrophage and T cell counts in younger but not aged mice, with sub-group analysis pointing towards a role for Trem2+ macrophage. The transcriptomic analysis identified MIF- and aging-dependent changes in lipid, cell respiration, and inflammation pathways, and key enriched genes such as Cpne7, Cd6, Plin1, Cd274 hinting towards effects on lesional T cells, lipids, and foamy macrophages. Moreover, Mif-deficient aged mice exhibited a distinct plasma cytokine/chemokine signature consistent with the notion that mediators known to drive inflamm’aging are either not down-regulated or even up- regulated in Mif-deficient aged mice compared to the corresponding younger ones. Lastly, Mif-deficiency favored formation of lymphocyte-rich peri-adventitial leukocyte clusters. While the causative contributions of these mechanistic pillars and their interplay will be subject to future scrutiny, our study suggests that atheroprotection due to global Mif-gene deficiency in atherogenic Apoe–/– mice is reduced upon advanced aging and identifies previously unrecognized cellular and molecular targets that could explain this phenotype shift. These observations enhance our understanding of inflamm’aging and MIF pathways in atherosclerosis and may have implications for translational MIF-directed strategies.

Project description:Systemic immune responses induced by chronic hypercholesterolemia contribute to the initiation, progression and complications of atherosclerosis. However, the consequences of an alternate high fat diet and the associated variations in plasma cholesterol levels on atherosclerosis are unknown. To address this relevant issue concerning common situations where dietary habits change over time, we developed a novel protocol in athero-prone mice that allowed us to compare the effects of alternate versus continuous high fat diet (HFD) on atherosclerosis, the overall period of time of exposure to HFD being similar between groups. We showed that alternate HFD lead to accelerated atherosclerosis in Ldlr-/- and Apoe-/- mice compared to continuous HFD. The pro-atherogenic effect of alternate HFD was also found in Apoe-/-Rag2-/- mice lacking T, B, and NKT cells, ruling out a role for the adaptive immune system in the observed phenotype. Using different complementary in vivo approaches, we found that lipid-rich diet discontinuation in alternate group downregulated Runx1, a negative regulator downstream of TLR-4 pathways. As a result, after re-exposure to HFD, myeloid progenitors were more sensitive to hypercholesterolemia leading to acute differentiation into IL-1b- producing immature neutrophils, which caused a state of emergency myelopoiesis. Consecutively, neutrophils markedly increased in the peripheral blood, infiltrated atherosclerotic lesions and locally released neutrophil extracellular traps. Anti-Ly6G neutrophil depletion abolished the pro-atherogenic effects of alternate HFD. Specific deletion of Il1b and Il1b receptor confirmed that the IL-1b signaling pathway was a major driver of the pro-inflammatory and pro-atherogenic neutrophil signature. Finally, treatment with anti-IL-1b neutralizing antibody or inflammasome inhibitor during re-exposure to HFD reversed the pro-atherogenic effects of alternate HFD. In summary, we showed that alternate HFD accelerates atherosclerosis through IL-1b-dependent neutrophil progenitor reprogramming.

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An atypical atherogenic chemokine that promotes advanced atherosclerosis and hepatic lipogenesis

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