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C/EBP? in bone marrow is essential for diet induced inflammation, cholesterol balance, and atherosclerosis.

ABSTRACT: BACKGROUND AND OBJECTIVE:Atherosclerosis is both a chronic inflammatory disease and a lipid metabolism disorder. C/EBP? is well documented for its role in the development of hematopoietic cells and integration of lipid metabolism. However, C/EBP?'s role in atherosclerotic progression has not been examined. We assessed the impact of hematopoietic CEBP? deletion in ApoE(-/-) mice on hyperlipidemia, inflammatory responses and lesion formation in the aorta. METHODS AND RESULTS:ApoE(-/-) mice were reconstituted with bone marrow cells derived from either WT or C/EBP?(-/-) mice and placed on low fat or high fat/high cholesterol diet for 11 weeks. Hematopoietic C/EBP? deletion in ApoE(-/-) mice reduced blood and hepatic lipids and gene expression of hepatic stearoyl CoA desaturase 1 and fatty acid synthase while expression of ATP binding cassette transporter G1, cholesterol 7-alpha-hydroxylase, and liver X receptor alpha genes were significantly increased. ApoE(-/-) mice reconstituted with C/EBP?(-/-) bone marrow cells also significantly reduced blood cytokine levels and reduced lesion area in aortic sinuses compared with ApoE(-/-) mice reconstituted with WT bone marrow cells. Silencing of C/EBP? in RAW264.7 macrophage cells prevented oxLDL-mediated foam cell formation and inflammatory cytokine secretion in conditioned medium. CONCLUSION:C/EBP? in hematopoietic cells is crucial to regulate diet-induced inflammation, hyperlipidemia and atherosclerosis development.

SUBMITTER: Rahman SM

PROVIDER: S-EPMC4907836 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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C/EBPβ in bone marrow is essential for diet induced inflammation, cholesterol balance, and atherosclerosis.

Rahman Shaikh M SM Baquero Karalee C KC Choudhury Mahua M Janssen Rachel C RC de la Houssaye Becky A BA Sun Ming M Miyazaki-Anzai Shinobu S Wang Shu S Moustaid-Moussa Naima N Miyazaki Makoto M Friedman Jacob E JE

Atherosclerosis 20160401

<h4>Background and objective</h4>Atherosclerosis is both a chronic inflammatory disease and a lipid metabolism disorder. C/EBPβ is well documented for its role in the development of hematopoietic cells and integration of lipid metabolism. However, C/EBPβ's role in atherosclerotic progression has not been examined. We assessed the impact of hematopoietic CEBPβ deletion in ApoE(-/-) mice on hyperlipidemia, inflammatory responses and lesion formation in the aorta.<h4>Methods and results</h4>ApoE(-/ ...[more]

PMID: 27072340

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Project description:Atherosclerosis is fueled by a failure to resolve lipid-driven inflammation within the vasculature that drives plaque formation. Therapeutic approaches to reverse atherosclerotic inflammation are needed to address the rising global burden of cardiovascular disease (CVD). Recently, metabolites have gained attention for their immunomodulatory properties, including itaconate, which is generated from the tricarboxylic acid-intermediate cis-aconitate by the enzyme Immune Responsive Gene 1 (IRG1/ACOD1). Here, we tested the therapeutic potential of the IRG1-itaconate axis for human atherosclerosis. Using single-cell RNA sequencing (scRNA-seq), we found that IRG1 is up-regulated in human coronary atherosclerotic lesions compared to patient-matched healthy vasculature, and in mouse models of atherosclerosis, where it is primarily expressed by plaque monocytes, macrophages, and neutrophils. Global or hematopoietic Irg1-deficiency in mice increases atherosclerosis burden, plaque macrophage and lipid content, and expression of the proatherosclerotic cytokine interleukin (IL)-1β. Mechanistically, absence of Irg1 increased macrophage lipid accumulation, and accelerated inflammation via increased neutrophil extracellular trap (NET) formation and NET-priming of the NLRP3-inflammasome in macrophages, resulting in increased IL-1β release. Conversely, supplementation of the Irg1-itaconate axis using 4-octyl itaconate (4-OI) beneficially remodeled advanced plaques and reduced lesional IL-1β levels in mice. To investigate the effects of 4-OI in humans, we leveraged an ex vivo systems-immunology approach for CVD drug discovery. Using CyTOF and scRNA-seq of peripheral blood mononuclear cells treated with plasma from CVD patients, we showed that 4-OI attenuates proinflammatory phospho-signaling and mediates anti-inflammatory rewiring of macrophage populations. Our data highlight the relevance of pursuing IRG1-itaconate axis supplementation as a therapeutic approach for atherosclerosis in humans.

Dataset Information

C/EBP? in bone marrow is essential for diet induced inflammation, cholesterol balance, and atherosclerosis.

Publications

C/EBPβ in bone marrow is essential for diet induced inflammation, cholesterol balance, and atherosclerosis.

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