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Depletion of FOXP3(+) regulatory T cells promotes hypercholesterolemia and atherosclerosis
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2013 (English)In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 123, no 3, 1323-1334 p.Article in journal (Refereed) Published
Abstract [en]

Atherosclerosis is a chronic inflammatory disease promoted by hyperlipidemia. Several studies support FOXP3-positive regulatory T cells (Tregs) as inhibitors of atherosclerosis; however, the mechanism underlying this protection remains elusive. To define the role of FOXP3-expressing Tregs in atherosclerosis, we used the DEREG mouse, which expresses the diphtheria toxin (DT) receptor under control of the Treg-specific Foxp3 promoter, allowing for specific ablation of FOXP3(+) Tregs. Lethally irradiated, atherosclerosis-prone, low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice received DEREG bone marrow and were injected with DT to eliminate FOXP3(+) Tregs. Depletion of Tregs caused a 2.1-fold increase in atherosclerosis without a concomitant increase in vascular inflammation. These mice also exhibited a 1.7-fold increase in plasma cholesterol and an atherogenic lipoprotein profile with increased levels of VLDL. Clearance of VLDL and chylomicron remnants was hampered, leading to accumulation of cholesterol-rich particles in the circulation. Functional and protein analyses complemented by gene expression array identified reduced protein expression of sortilin-1 in liver and increased plasma enzyme activity of lipoprotein lipase, hepatic lipase, and phospholipid transfer protein as mediators of the altered lipid phenotype. These results demonstrate that FOXP3(+) Tregs inhibit atherosclerosis by modulating lipoprotein metabolism.

Place, publisher, year, edition, pages
2013. Vol. 123, no 3, 1323-1334 p.
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Other Basic Medicine
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URN: urn:nbn:se:umu:diva-67961DOI: 10.1172/JCI63891ISI: 000315749400041OAI: oai:DiVA.org:umu-67961DiVA: diva2:615920
Available from: 2013-04-12 Created: 2013-04-09 Last updated: 2017-12-06Bibliographically approved

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Nilsson, Stefan KOlivecrona, Gunilla

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