Oxidized Low-Density Lipoprotein Receptor in Lymphocytes Prevents Atherosclerosis and Predicts Subclinical Disease

Background: Although the role of Th17 and regulatory T cells in the progression of atherosclerosis has been highlighted in recent years, their molecular mediators remain elusive. We aimed to evaluate the association between the CD69 receptor, a regulator of Th17/regulatory T cell immunity, and ather...

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Autores: Tsilingiri, K, de la Fuente, H, Relano, M, Sanchez-Diaz, R, Rodriguez, C, Crespo, J, Sanchez-Cabo, F, Dopazo, A, Alonso-Lebrero, JL, Vara, A, Vazquez, J, Casasnovas, JM, Alfonso, F, Ibanez, B, Fuster, V, Martinez-Gonzalez, J, Martin, P, Sanchez-Madrid, F
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2019
País:España
Recursos:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repositorio:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:iibsantpau.fundanetsuite.com:p3043
Acesso em linha:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=3043
http://ddd.uab.cat/record/223050
Access Level:acceso abierto
Palavra-chave:atherosclerosis
CD69 antigen
oxidized low density lipoprotein
regulatory T lymphocytes
Th17 cells
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spelling Oxidized Low-Density Lipoprotein Receptor in Lymphocytes Prevents Atherosclerosis and Predicts Subclinical DiseaseTsilingiri, Kde la Fuente, HRelano, MSanchez-Diaz, RRodriguez, CCrespo, JSanchez-Cabo, FDopazo, AAlonso-Lebrero, JLVara, AVazquez, JCasasnovas, JMAlfonso, FIbanez, BFuster, VMartinez-Gonzalez, JMartin, PSanchez-Madrid, FatherosclerosisCD69 antigenoxidized low density lipoproteinregulatory T lymphocytesTh17 cellsBackground: Although the role of Th17 and regulatory T cells in the progression of atherosclerosis has been highlighted in recent years, their molecular mediators remain elusive. We aimed to evaluate the association between the CD69 receptor, a regulator of Th17/regulatory T cell immunity, and atherosclerosis development in animal models and in patients with subclinical disease. Methods: Low-density lipoprotein receptor-deficient chimeric mice expressing or not expressing CD69 on either myeloid or lymphoid cells were subjected to a high fat diet. In vitro functional assays with human T cells were performed to decipher the mechanism of the observed phenotypes. Expression of CD69 and NR4A nuclear receptors was evaluated by reverse transcription-polymerase chain reaction in 305 male participants of the PESA study (Progression of Early Subclinical Atherosclerosis) with extensive (n=128) or focal (n=55) subclinical atherosclerosis and without disease (n=122). Results: After a high fat diet, mice lacking CD69 on lymphoid cells developed large atheroma plaque along with an increased Th17/regulatory T cell ratio in blood. Oxidized low-density lipoprotein was shown to bind specifically and functionally to CD69 on human T lymphocytes, inhibiting the development of Th17 cells through the activation of NR4A nuclear receptors. Participants of the PESA study with evidence of subclinical atherosclerosis displayed a significant CD69 and NR4A1 mRNA downregulation in peripheral blood leukocytes compared with participants without disease. The expression of CD69 remained associated with the risk of subclinical atherosclerosis in an adjusted multivariable logistic regression model (odds ratio, 0.62; 95% CI, 0.40-0.94; P=0.006) after adjustment for traditional risk factors, the expression of NR4A1, the level of oxidized low-density lipoprotein, and the counts of different leucocyte subsets. Conclusions: CD69 depletion from the lymphoid compartment promotes a Th17/regulatory T cell imbalance and exacerbates the development of atherosclerosis. CD69 binding to oxidized low-density lipoprotein on T cells induces the expression of anti-inflammatory transcription factors. Data from a cohort of the PESA study with subclinical atherosclerosis indicate that CD69 expression in PBLs inversely correlates with the presence of disease. The expression of CD69 remained an independent predictor of subclinical atherosclerosis after adjustment for traditional risk factors.LIPPINCOTT WILLIAMS & WILKINS2019info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=3043http://ddd.uab.cat/record/223050CIRCULATIONISSN: 00097322ISSNe: 15244539reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pauinstname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)Inglésinfo:eu-repo/semantics/openAccessoai:iibsantpau.fundanetsuite.com:p30432026-06-14T12:41:47Z
dc.title.none.fl_str_mv Oxidized Low-Density Lipoprotein Receptor in Lymphocytes Prevents Atherosclerosis and Predicts Subclinical Disease
title Oxidized Low-Density Lipoprotein Receptor in Lymphocytes Prevents Atherosclerosis and Predicts Subclinical Disease
spellingShingle Oxidized Low-Density Lipoprotein Receptor in Lymphocytes Prevents Atherosclerosis and Predicts Subclinical Disease
Tsilingiri, K
atherosclerosis
CD69 antigen
oxidized low density lipoprotein
regulatory T lymphocytes
Th17 cells
title_short Oxidized Low-Density Lipoprotein Receptor in Lymphocytes Prevents Atherosclerosis and Predicts Subclinical Disease
title_full Oxidized Low-Density Lipoprotein Receptor in Lymphocytes Prevents Atherosclerosis and Predicts Subclinical Disease
title_fullStr Oxidized Low-Density Lipoprotein Receptor in Lymphocytes Prevents Atherosclerosis and Predicts Subclinical Disease
title_full_unstemmed Oxidized Low-Density Lipoprotein Receptor in Lymphocytes Prevents Atherosclerosis and Predicts Subclinical Disease
title_sort Oxidized Low-Density Lipoprotein Receptor in Lymphocytes Prevents Atherosclerosis and Predicts Subclinical Disease
dc.creator.none.fl_str_mv Tsilingiri, K
de la Fuente, H
Relano, M
Sanchez-Diaz, R
Rodriguez, C
Crespo, J
Sanchez-Cabo, F
Dopazo, A
Alonso-Lebrero, JL
Vara, A
Vazquez, J
Casasnovas, JM
Alfonso, F
Ibanez, B
Fuster, V
Martinez-Gonzalez, J
Martin, P
Sanchez-Madrid, F
author Tsilingiri, K
author_facet Tsilingiri, K
de la Fuente, H
Relano, M
Sanchez-Diaz, R
Rodriguez, C
Crespo, J
Sanchez-Cabo, F
Dopazo, A
Alonso-Lebrero, JL
Vara, A
Vazquez, J
Casasnovas, JM
Alfonso, F
Ibanez, B
Fuster, V
Martinez-Gonzalez, J
Martin, P
Sanchez-Madrid, F
author_role author
author2 de la Fuente, H
Relano, M
Sanchez-Diaz, R
Rodriguez, C
Crespo, J
Sanchez-Cabo, F
Dopazo, A
Alonso-Lebrero, JL
Vara, A
Vazquez, J
Casasnovas, JM
Alfonso, F
Ibanez, B
Fuster, V
Martinez-Gonzalez, J
Martin, P
Sanchez-Madrid, F
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv atherosclerosis
CD69 antigen
oxidized low density lipoprotein
regulatory T lymphocytes
Th17 cells
topic atherosclerosis
CD69 antigen
oxidized low density lipoprotein
regulatory T lymphocytes
Th17 cells
description Background: Although the role of Th17 and regulatory T cells in the progression of atherosclerosis has been highlighted in recent years, their molecular mediators remain elusive. We aimed to evaluate the association between the CD69 receptor, a regulator of Th17/regulatory T cell immunity, and atherosclerosis development in animal models and in patients with subclinical disease. Methods: Low-density lipoprotein receptor-deficient chimeric mice expressing or not expressing CD69 on either myeloid or lymphoid cells were subjected to a high fat diet. In vitro functional assays with human T cells were performed to decipher the mechanism of the observed phenotypes. Expression of CD69 and NR4A nuclear receptors was evaluated by reverse transcription-polymerase chain reaction in 305 male participants of the PESA study (Progression of Early Subclinical Atherosclerosis) with extensive (n=128) or focal (n=55) subclinical atherosclerosis and without disease (n=122). Results: After a high fat diet, mice lacking CD69 on lymphoid cells developed large atheroma plaque along with an increased Th17/regulatory T cell ratio in blood. Oxidized low-density lipoprotein was shown to bind specifically and functionally to CD69 on human T lymphocytes, inhibiting the development of Th17 cells through the activation of NR4A nuclear receptors. Participants of the PESA study with evidence of subclinical atherosclerosis displayed a significant CD69 and NR4A1 mRNA downregulation in peripheral blood leukocytes compared with participants without disease. The expression of CD69 remained associated with the risk of subclinical atherosclerosis in an adjusted multivariable logistic regression model (odds ratio, 0.62; 95% CI, 0.40-0.94; P=0.006) after adjustment for traditional risk factors, the expression of NR4A1, the level of oxidized low-density lipoprotein, and the counts of different leucocyte subsets. Conclusions: CD69 depletion from the lymphoid compartment promotes a Th17/regulatory T cell imbalance and exacerbates the development of atherosclerosis. CD69 binding to oxidized low-density lipoprotein on T cells induces the expression of anti-inflammatory transcription factors. Data from a cohort of the PESA study with subclinical atherosclerosis indicate that CD69 expression in PBLs inversely correlates with the presence of disease. The expression of CD69 remained an independent predictor of subclinical atherosclerosis after adjustment for traditional risk factors.
publishDate 2019
dc.date.none.fl_str_mv 2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=3043
http://ddd.uab.cat/record/223050
url https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=3043
http://ddd.uab.cat/record/223050
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv LIPPINCOTT WILLIAMS & WILKINS
publisher.none.fl_str_mv LIPPINCOTT WILLIAMS & WILKINS
dc.source.none.fl_str_mv CIRCULATION
ISSN: 00097322
ISSNe: 15244539
reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
instname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
instname_str Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
reponame_str r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
collection r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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