An atypical atherogenic chemokine that promotes advanced atherosclerosis and hepatic lipogenesis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1183316 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31264474_1.fastq.gz | Fastqsanger.gz | |||
| SRR31264474_2.fastq.gz | Fastqsanger.gz | |||
| SRR31264475_1.fastq.gz | Fastqsanger.gz | |||
| SRR31264475_2.fastq.gz | Fastqsanger.gz | |||
| SRR31264476_1.fastq.gz | Fastqsanger.gz |
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Similar Datasets
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.
2025-03-13 | GSE281285 | GEO
Project description:An atypical atherogenic chemokine that promotes advanced athero¬sclerosis and hepatic lipogenesis
| PRJNA1211655 | ENA
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.
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Project description: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.
| S-EPMC11889166 | biostudies-literature
Project description:The atypical chemokine receptor 3 (ACKR3) plays a pivotal role in directing the migration of various cellular populations and its over-expression in various tumors promotes cell proliferation and invasiveness. The intracellular cellular pathways transducing ACKR3-dependent effects remain poorly characterized, an issue we addressed by characterizing the the interactome of recombinant ACKR3 expressed in HEK293T cells. Among the ACKR3-interacting proteins identified, we focused on the gap junction protein Connexin 43 (Cx43).
2020-07-07 | PXD016978 | Pride
Project description:Healthy individuals of African ancestry have neutropenia that has been linked with the variant rs2814778(G) of the gene encoding atypical chemokine receptor 1 (ACKR1). This polymorphism selectively abolishes the erythroid cell expression of ACKR1, causing Duffy-negative phenotype. Here we describe an unexpected fundamental role that ACKR1 plays in hematopoiesis and provide the mechanism linking its absence with neutropenia. Nucleated erythroid cells highly expressed ACKR1, which facilitated their direct contacts with the hematopoietic stem cells. The absence of erythroid ACKR1 altered murine hematopoiesis, including stem and progenitor cells, ultimately giving rise to phenotypically distinct neutrophils, which readily left the circulation, causing neutropenia. Duffy-negative individuals developed a distinct profile of neutrophil effector molecules closely reflecting that in the ACKR1-deficient mice. Thus, alternative physiological patterns of hematopoiesis and bone marrow cell outputs depend on the expression of ACKR1 in the erythroid lineage providing major implications for the selection advantages that have resulted in the paramount fixation of the rs2814778(G) polymorphism in Africa.
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Project description:Placental chemokine compartmentalisation is essential for effective embryonic macrophage development
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2025-05-07 | PXD054290 | Pride
Project description:To address the molecular basis for atherogenic diet-induced liver injury, we performed microarray analysis using livers at early (6 weeks) and pre-cirrhosis stages (24 weeks) in the development of steatohepatitis. The Atherogenic diet up-regulated the gene expression for fatty acid synthesis, inflammatory cytokines, oxidative stress, and fibrosis, and with down-regulation of fatty acid beta-oxidation. The addition of a high-fat component to the Atherogenic diet up-regulated the gene expression for fatty acid synthesis and transport pathways and down-regulated some of the antioxidant genes. Keywords: time-course
2006-09-19 | GSE5852 | GEO
Project description:Apolipoprotein-B (APOB)-containing lipoproteins cause atherosclerosis. Whether the vasculature is initially responding site, or if atherogenic-dyslipidemia affects other organs simultaneously, is unknown. Here we show that the liver responds to a dyslipidemic insult based on inducible models of familial hypercholesterolemia and APOB tracing. An acute transition to atherogenic APOB-lipoprotein levels resulted in uptake by Kupffer cells and rapid accumulation of triglycerides and cholesterol in the liver. Bulk and single-cell RNA-seq revealed an Kupffer cell-specific transcriptional program that was not activated by a high-fat diet alone, or detected in standard liver function or pathological assays, even in the presence of fulminant atherosclerosis. Depletion of Kupffer cells altered the dynamic of plasma and liver lipid concentrations, indicating that these liver macrophages help restrain and buffer atherogenic lipoproteins, whilst simultaneously secreting atherosclerosis-modulating factors into plasma. Our results place Kupffer cells as key sentinels in organizing systemic responses to lipoproteins at the initiation of atherosclerosis.
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