Depletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosis

Roland Klingenberg, Norbert Gerdes, Robert M Badeau, Anton Gisterå, Daniela Strodthoff, Daniel F J Ketelhuth, Anna M Lundberg, Mats Rudling, Stefan K Nilsson, Gunilla Olivecrona, Stefan Zoller, Christine Lohmann, Thomas F Lüscher, Matti Jauhiainen, Tim Sparwasser, Göran K Hansson

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Abstrakt

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.

OriginalsprogEngelsk
TidsskriftJournal of Clinical Investigation
Vol/bind123
Udgave nummer3
Sider (fra-til)1323-1334
ISSN0021-9738
DOI
StatusUdgivet - 1. mar. 2013
Udgivet eksterntJa

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