Depletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosis

被引:312
作者
Klingenberg, Roland [1 ,2 ,3 ]
Gerdes, Norbert [1 ,4 ,5 ]
Badeau, Robert M. [1 ]
Gistera, Anton [1 ]
Strodthoff, Daniela [1 ]
Ketelhuth, Daniel F. J. [1 ]
Lundberg, Anna M. [1 ]
Rudling, Mats [6 ,7 ]
Nilsson, Stefan K. [8 ]
Olivecrona, Gunilla [8 ]
Zoller, Stefan [9 ]
Lohmann, Christine [2 ,3 ]
Luescher, Thomas F. [2 ,3 ]
Jauhiainen, Matti [10 ,11 ]
Sparwasser, Tim [12 ]
Hansson, Goran K. [1 ]
机构
[1] Karolinska Inst, Karolinska Univ Hosp, Dept Med, Ctr Mol Med, Stockholm, Sweden
[2] Univ Zurich Hosp, Dept Cardiol, Ctr Cardiovasc, CH-8091 Zurich, Switzerland
[3] Univ Zurich, Inst Physiol, Zurich Ctr Integrat Human Physiol ZIHP, Zurich, Switzerland
[4] Univ Munich, Inst Cardiovasc Prevent IPEK, Munich, Germany
[5] Univ Amsterdam, Acad Med Ctr, Dept Med Biochem, NL-1105 AZ Amsterdam, Netherlands
[6] Karolinska Univ Hosp Huddinge, Karolinska Inst, Dept Endocrinol, Dept Med,Metab Unit,Metab & Diabet & Mol Nutr Uni, Stockholm, Sweden
[7] Karolinska Univ Hosp Huddinge, Karolinska Inst, Ctr Biosci & Nutr, Stockholm, Sweden
[8] Umea Univ, Dept Med Biosci Physiol Chem, Umea, Sweden
[9] Fed Inst Technol ETH, Genet Divers Ctr, Zurich, Switzerland
[10] Natl Inst Hlth & Welf THL, Dept Chron Dis Prevent, Publ Hlth Genom Res Unit, Helsinki, Finland
[11] Inst Mol Med Finland, Biomedicum, Helsinki, Finland
[12] TWINCORE Ctr Expt & Clin Infect Res, Inst Infect Immunol, Hannover, Germany
基金
瑞典研究理事会;
关键词
PHOSPHOLIPID-TRANSFER PROTEIN; APOLIPOPROTEIN-B SECRETION; LIPOPROTEIN-LIPASE; TRANSGENIC MICE; PLASMA; DISEASE; PLTP; INTERLEUKIN-10; ATHEROGENESIS; INFLAMMATION;
D O I
10.1172/JCI63891
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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.
引用
收藏
页码:1323 / 1334
页数:12
相关论文
共 53 条
  • [1] Natural regulatory T cells control the development of atherosclerosis in mice
    Ait-Oufella, H
    Salomon, BL
    Potteaux, S
    Robertson, AKL
    Gourdy, P
    Zoll, J
    Merval, R
    Esposito, B
    Cohen, JL
    Fisson, S
    Flavell, RA
    Hansson, GK
    Klatzmann, D
    Tedgui, A
    Mallat, Z
    [J]. NATURE MEDICINE, 2006, 12 (02) : 178 - 180
  • [2] Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins
    Baigent, C
    Keech, A
    Kearney, PM
    Blackwell, L
    Buck, G
    Pollicino, C
    Kirby, A
    Sourjina, T
    Peto, R
    Collins, R
    Simes, J
    [J]. LANCET, 2005, 366 (9493) : 1267 - 1278
  • [3] Optimal Isolation of Functional Foxp3+ Induced Regulatory T Cells Using DEREG Mice
    Baru, Abdul Mannan
    Untucht, Christopher
    Ganesh, Venkateswaran
    Hesse, Christina
    Mayer, Christian T.
    Sparwasser, Tim
    [J]. PLOS ONE, 2012, 7 (09):
  • [4] BENGTSSONOLIVECRONA G, 1991, METHOD ENZYMOL, V197, P345
  • [5] Forms of lipoprotein lipase in rat tissues: In adipose tissue the proportion of inactive lipase increases on fasting
    Bergo, M
    Olivecrona, G
    Olivecrona, T
    [J]. BIOCHEMICAL JOURNAL, 1996, 313 : 893 - 898
  • [6] DAVID: Database for annotation, visualization, and integrated discovery
    Dennis, G
    Sherman, BT
    Hosack, DA
    Yang, J
    Gao, W
    Lane, HC
    Lempicki, RA
    [J]. GENOME BIOLOGY, 2003, 4 (09)
  • [7] Foxp3 Programs the Development and Function of CD4+CD25+ Regulatory T Cells (Reprinted from vol 4, pg 330-336, 2003)
    Fontenot, Jason D.
    Gavin, Marc A.
    Rudensky, Alexander Y.
    [J]. JOURNAL OF IMMUNOLOGY, 2017, 198 (03) : 986 - 992
  • [8] Mechanisms of Disease: the evolving role of regulatory T cells in atherosclerosis
    George, Jacob
    [J]. NATURE CLINICAL PRACTICE CARDIOVASCULAR MEDICINE, 2008, 5 (09): : 531 - 540
  • [9] Specific abrogation of transforming growth factor-β signaling in T cells alters atherosclerotic lesion size and composition in mice
    Gojova, A
    Brun, V
    Esposito, B
    Cottrez, F
    Gourdy, P
    Ardouin, P
    Tedgui, A
    Mallat, Z
    Groux, H
    [J]. BLOOD, 2003, 102 (12) : 4052 - 4058
  • [10] Impaired regulatory T-cell response and enhanced atherosclerosis in the absence of inducible costimulatory molecule
    Gotsman, Israel
    Grabie, Nir
    Gupta, Rajat
    Dacosta, Rosa
    MacConmara, Malcolm
    Lederer, James
    Sukhova, Galina
    Witztum, Joseph L.
    Sharpe, Arlene H.
    Lichtman, Andrew H.
    [J]. CIRCULATION, 2006, 114 (19) : 2047 - 2055