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Diet-induced dyslipidemia induces metabolic and migratory adaptations in regulatory T cells

AIMS: A hallmark of advanced atherosclerosis is inadequate immunosuppression by regulatory T (Treg) cells inside atherosclerotic lesions. Dyslipidemia has been suggested to alter Treg cell migration by affecting the expression of specific membrane proteins, thereby decreasing Treg cell migration tow...

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Autores principales: Amersfoort, Jacob, Schaftenaar, Frank H, Douna, Hidde, van Santbrink, Peter J, van Puijvelde, Gijs H M, Slütter, Bram, Foks, Amanda C, Harms, Amy, Moreno-Gordaliza, Estefania, Wang, Yanyan, Hankemeier, Thomas, Bot, Ilze, Chi, Hongbo, Kuiper, Johan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064436/
https://www.ncbi.nlm.nih.gov/pubmed/32653923
http://dx.doi.org/10.1093/cvr/cvaa208
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author Amersfoort, Jacob
Schaftenaar, Frank H
Douna, Hidde
van Santbrink, Peter J
van Puijvelde, Gijs H M
Slütter, Bram
Foks, Amanda C
Harms, Amy
Moreno-Gordaliza, Estefania
Wang, Yanyan
Hankemeier, Thomas
Bot, Ilze
Chi, Hongbo
Kuiper, Johan
author_facet Amersfoort, Jacob
Schaftenaar, Frank H
Douna, Hidde
van Santbrink, Peter J
van Puijvelde, Gijs H M
Slütter, Bram
Foks, Amanda C
Harms, Amy
Moreno-Gordaliza, Estefania
Wang, Yanyan
Hankemeier, Thomas
Bot, Ilze
Chi, Hongbo
Kuiper, Johan
author_sort Amersfoort, Jacob
collection PubMed
description AIMS: A hallmark of advanced atherosclerosis is inadequate immunosuppression by regulatory T (Treg) cells inside atherosclerotic lesions. Dyslipidemia has been suggested to alter Treg cell migration by affecting the expression of specific membrane proteins, thereby decreasing Treg cell migration towards atherosclerotic lesions. Besides membrane proteins, cellular metabolism has been shown to be a crucial factor in Treg cell migration. We aimed to determine whether dyslipidemia contributes to altered migration of Treg cells, in part, by affecting cellular metabolism. METHODS AND RESULTS: Dyslipidemia was induced by feeding Ldlr(−/−) mice a western-type diet for 16–20 weeks and intrinsic changes in Treg cells affecting their migration and metabolism were examined. Dyslipidemia was associated with altered mTORC2 signalling in Treg cells, decreased expression of membrane proteins involved in migration, including CD62L, CCR7, and S1Pr1, and decreased Treg cell migration towards lymph nodes. Furthermore, we discovered that diet-induced dyslipidemia inhibited mTORC1 signalling, induced PPARδ activation and increased fatty acid (FA) oxidation in Treg cells. Moreover, mass-spectrometry analysis of serum from Ldlr(−/−) mice with normolipidemia or dyslipidemia showed increases in multiple PPARδ ligands during dyslipidemia. Treatment with a synthetic PPARδ agonist increased the migratory capacity of Treg cells in vitro and in vivo in an FA oxidation-dependent manner. Furthermore, diet-induced dyslipidemia actually enhanced Treg cell migration into the inflamed peritoneum and into atherosclerotic lesions in vitro. CONCLUSION: Altogether, our findings implicate that dyslipidemia does not contribute to atherosclerosis by impairing Treg cell migration as dyslipidemia associated with an effector-like migratory phenotype in Treg cells.
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spelling pubmed-80644362021-04-29 Diet-induced dyslipidemia induces metabolic and migratory adaptations in regulatory T cells Amersfoort, Jacob Schaftenaar, Frank H Douna, Hidde van Santbrink, Peter J van Puijvelde, Gijs H M Slütter, Bram Foks, Amanda C Harms, Amy Moreno-Gordaliza, Estefania Wang, Yanyan Hankemeier, Thomas Bot, Ilze Chi, Hongbo Kuiper, Johan Cardiovasc Res Original Articles AIMS: A hallmark of advanced atherosclerosis is inadequate immunosuppression by regulatory T (Treg) cells inside atherosclerotic lesions. Dyslipidemia has been suggested to alter Treg cell migration by affecting the expression of specific membrane proteins, thereby decreasing Treg cell migration towards atherosclerotic lesions. Besides membrane proteins, cellular metabolism has been shown to be a crucial factor in Treg cell migration. We aimed to determine whether dyslipidemia contributes to altered migration of Treg cells, in part, by affecting cellular metabolism. METHODS AND RESULTS: Dyslipidemia was induced by feeding Ldlr(−/−) mice a western-type diet for 16–20 weeks and intrinsic changes in Treg cells affecting their migration and metabolism were examined. Dyslipidemia was associated with altered mTORC2 signalling in Treg cells, decreased expression of membrane proteins involved in migration, including CD62L, CCR7, and S1Pr1, and decreased Treg cell migration towards lymph nodes. Furthermore, we discovered that diet-induced dyslipidemia inhibited mTORC1 signalling, induced PPARδ activation and increased fatty acid (FA) oxidation in Treg cells. Moreover, mass-spectrometry analysis of serum from Ldlr(−/−) mice with normolipidemia or dyslipidemia showed increases in multiple PPARδ ligands during dyslipidemia. Treatment with a synthetic PPARδ agonist increased the migratory capacity of Treg cells in vitro and in vivo in an FA oxidation-dependent manner. Furthermore, diet-induced dyslipidemia actually enhanced Treg cell migration into the inflamed peritoneum and into atherosclerotic lesions in vitro. CONCLUSION: Altogether, our findings implicate that dyslipidemia does not contribute to atherosclerosis by impairing Treg cell migration as dyslipidemia associated with an effector-like migratory phenotype in Treg cells. Oxford University Press 2020-07-11 /pmc/articles/PMC8064436/ /pubmed/32653923 http://dx.doi.org/10.1093/cvr/cvaa208 Text en © The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Original Articles
Amersfoort, Jacob
Schaftenaar, Frank H
Douna, Hidde
van Santbrink, Peter J
van Puijvelde, Gijs H M
Slütter, Bram
Foks, Amanda C
Harms, Amy
Moreno-Gordaliza, Estefania
Wang, Yanyan
Hankemeier, Thomas
Bot, Ilze
Chi, Hongbo
Kuiper, Johan
Diet-induced dyslipidemia induces metabolic and migratory adaptations in regulatory T cells
title Diet-induced dyslipidemia induces metabolic and migratory adaptations in regulatory T cells
title_full Diet-induced dyslipidemia induces metabolic and migratory adaptations in regulatory T cells
title_fullStr Diet-induced dyslipidemia induces metabolic and migratory adaptations in regulatory T cells
title_full_unstemmed Diet-induced dyslipidemia induces metabolic and migratory adaptations in regulatory T cells
title_short Diet-induced dyslipidemia induces metabolic and migratory adaptations in regulatory T cells
title_sort diet-induced dyslipidemia induces metabolic and migratory adaptations in regulatory t cells
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064436/
https://www.ncbi.nlm.nih.gov/pubmed/32653923
http://dx.doi.org/10.1093/cvr/cvaa208
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