Depletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosis.

2.50
Hdl Handle:
http://hdl.handle.net/10033/296985
Title:
Depletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosis.
Authors:
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; Zoller, Stefan; Lohmann, Christine; Lüscher, Thomas F; Jauhiainen, Matti; Sparwasser, Tim; Hansson, Göran K
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.
Affiliation:
Center for Molecular Medicine, Department of Medicine, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
Citation:
Depletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosis. 2013, 123 (3):1323-34 J. Clin. Invest.
Journal:
The Journal of clinical investigation
Issue Date:
1-Mar-2013
URI:
http://hdl.handle.net/10033/296985
DOI:
10.1172/JCI63891
PubMed ID:
23426179
Type:
Article
Language:
en
ISSN:
1558-8238
Appears in Collections:
publications of the TwinCore unit Infection immunology

Full metadata record

DC FieldValue Language
dc.contributor.authorKlingenberg, Rolanden_GB
dc.contributor.authorGerdes, Norberten_GB
dc.contributor.authorBadeau, Robert Men_GB
dc.contributor.authorGisterå, Antonen_GB
dc.contributor.authorStrodthoff, Danielaen_GB
dc.contributor.authorKetelhuth, Daniel F Jen_GB
dc.contributor.authorLundberg, Anna Men_GB
dc.contributor.authorRudling, Matsen_GB
dc.contributor.authorNilsson, Stefan Ken_GB
dc.contributor.authorOlivecrona, Gunillaen_GB
dc.contributor.authorZoller, Stefanen_GB
dc.contributor.authorLohmann, Christineen_GB
dc.contributor.authorLüscher, Thomas Fen_GB
dc.contributor.authorJauhiainen, Mattien_GB
dc.contributor.authorSparwasser, Timen_GB
dc.contributor.authorHansson, Göran Ken_GB
dc.date.accessioned2013-07-24T14:44:31Z-
dc.date.available2013-07-24T14:44:31Z-
dc.date.issued2013-03-01-
dc.identifier.citationDepletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosis. 2013, 123 (3):1323-34 J. Clin. Invest.en_GB
dc.identifier.issn1558-8238-
dc.identifier.pmid23426179-
dc.identifier.doi10.1172/JCI63891-
dc.identifier.urihttp://hdl.handle.net/10033/296985-
dc.description.abstractAtherosclerosis 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.en_GB
dc.language.isoenen
dc.rightsArchived with thanks to The Journal of clinical investigationen_GB
dc.subject.meshAnimalsen_GB
dc.subject.meshAortaen_GB
dc.subject.meshAtherosclerosisen_GB
dc.subject.meshCells, Cultureden_GB
dc.subject.meshForkhead Transcription Factorsen_GB
dc.subject.meshHypercholesterolemiaen_GB
dc.subject.meshLipaseen_GB
dc.subject.meshLipid Metabolismen_GB
dc.subject.meshLipidsen_GB
dc.subject.meshLipoproteins, VLDLen_GB
dc.subject.meshLiveren_GB
dc.subject.meshLymphocyte Depletionen_GB
dc.subject.meshMaleen_GB
dc.subject.meshMiceen_GB
dc.subject.meshMice, Inbred C57BLen_GB
dc.subject.meshMice, Transgenicen_GB
dc.subject.meshOligonucleotide Array Sequence Analysisen_GB
dc.subject.meshPhospholipid Transfer Proteinsen_GB
dc.subject.meshReceptors, LDLen_GB
dc.subject.meshT-Lymphocytes, Regulatoryen_GB
dc.subject.meshTranscriptomeen_GB
dc.titleDepletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosis.en
dc.typeArticleen
dc.contributor.departmentCenter for Molecular Medicine, Department of Medicine, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.en_GB
dc.identifier.journalThe Journal of clinical investigationen_GB

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