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Depletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosis.
Klingenberg, Roland Gerdes, Norbert Badeau, Robert M Gisterå, Anton Strodthoff, Daniela Ketelhuth, Daniel F J Lundberg, Anna M Rudling, Mats Nilsson, Stefan K Olivecrona, Gunilla
Klingenberg, Roland
Gerdes, Norbert
Badeau, Robert M
Gisterå, Anton
Strodthoff, Daniela
Ketelhuth, Daniel F J
Lundberg, Anna M
Rudling, Mats
Nilsson, Stefan K
Olivecrona, Gunilla
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2013-03-01
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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-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.
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Depletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosis. 2013, 123 (3):1323-34 J. Clin. Invest.
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en
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1558-8238
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Archived with thanks to The Journal of clinical investigation