Depletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosis
Roland Klingenberg, … , Tim Sparwasser, Göran K. Hansson
Roland Klingenberg, … , Tim Sparwasser, Göran K. Hansson
Published February 15, 2013
Citation Information: J Clin Invest. 2013;123(3):1323-1334. https://doi.org/10.1172/JCI63891.
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Research Article Cardiology

Depletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosis

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.

Authors

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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Figure 8

Effects of Treg depletion on sortilin-1, LPL, HL, and PLTP.

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Effects of Treg depletion on sortilin-1, LPL, HL, and PLTP. (A) Immunobl...
(A) Immunoblot of liver tissue showing sortilin-1 protein in DT- or PBS-treated DEREG/Ldlr–/– mice. Full uncut images of sortilin-1 and tubulin immunoblots are shown in Supplemental Figure 7. (B) Scattergram shows individual values expressed as a ratio of sortilin-1 protein expression to α–tubulin protein expression. (C) LPL activity in postheparin plasma was measured using [3H]-labeled triolein in an emulsion with Intralipid 10% composition as the enzyme substrate; n = 10 (PBS); n = 9 (DT). (D) HL activity in postheparin plasma was measured using a gum arabic–stabilized emulsion; n = 10 (PBS); n = 9 (DT). (E) PLTP activity was measured using an exogenous lipoprotein-independent phospholipid transfer assay; n = 10 (PBS); n = 10 (DT). All data are from DEREG/Ldlr–/– mice treated for 8 weeks with DT or PBS. Mean ± SEM is shown. *P < 0.05; **P < 0.01.