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Depletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosis.
- Source :
-
Journal of Clinical Investigation . Mar2013, Vol. 123 Issue 3, p1323-1334. 12p. 1 Chart, 8 Graphs. - Publication Year :
- 2013
-
Abstract
- 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-den-sity 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 concomi-tant 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 rem-nants 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 123
- Issue :
- 3
- Database :
- Academic Search Index
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- 85973891
- Full Text :
- https://doi.org/10.1172/JCI63891