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...
| Autores: | , , , , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2019 |
| País: | España |
| Institución: | Consejo Superior de Investigaciones Científicas (CSIC) |
| Repositorio: | DIGITAL.CSIC. Repositorio Institucional del CSIC |
| OAI Identifier: | oai:digital.csic.es:10261/201708 |
| Acceso en línea: | http://hdl.handle.net/10261/201708 |
| Access Level: | acceso abierto |
| Palabra clave: | Atherosclerosis CD69 antigen Oxidized low density lipoprotein Regulatory T Lymphocytes Th17 cells |
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| 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, Katerina 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, Katerina Fuente, Hortensia de la Relaño, Marta Sánchez-Díaz, Raquel Rodríguez-Sinovas, Cristina Crespo, Javier Sánchez-Cabo, Fátima Dopazo, Ana Alonso-Lebrero, José Luis Vara, Alicia Vázquez, Jesús Casasnovas, José María Alfonso, Fernando Ibáñez, Borja Fuster, Valentín Martínez-González, José Martín, Pilar Sánchez-Madrid, Francisco |
| author |
Tsilingiri, Katerina |
| author_facet |
Tsilingiri, Katerina Fuente, Hortensia de la Relaño, Marta Sánchez-Díaz, Raquel Rodríguez-Sinovas, Cristina Crespo, Javier Sánchez-Cabo, Fátima Dopazo, Ana Alonso-Lebrero, José Luis Vara, Alicia Vázquez, Jesús Casasnovas, José María Alfonso, Fernando Ibáñez, Borja Fuster, Valentín Martínez-González, José Martín, Pilar Sánchez-Madrid, Francisco |
| author_role |
author |
| author2 |
Fuente, Hortensia de la Relaño, Marta Sánchez-Díaz, Raquel Rodríguez-Sinovas, Cristina Crespo, Javier Sánchez-Cabo, Fátima Dopazo, Ana Alonso-Lebrero, José Luis Vara, Alicia Vázquez, Jesús Casasnovas, José María Alfonso, Fernando Ibáñez, Borja Fuster, Valentín Martínez-González, José Martín, Pilar Sánchez-Madrid, Francisco |
| author2_role |
author author author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Agencia Estatal de Investigación (España) Ministerio de Economía y Competitividad (España) Ministerio de Ciencia, Innovación y Universidades (España) Instituto de Salud Carlos III Red Temática de Investigación Cooperativa en Enfermedades Cardiovasculares (España) European Research Council Fundació La Marató de TV3 Comunidad de Madrid European Commission Centro Nacional de Investigaciones Cardiovasculares (España) Fundación Pro CNIC Banco Santander Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72] |
| 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 2020 2020 2020 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article http://purl.org/coar/resource_type/c_6501 Publisher's version info:eu-repo/semantics/publishedVersion |
| format |
article |
| status_str |
publishedVersion |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/10261/201708 |
| url |
http://hdl.handle.net/10261/201708 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
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#PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/SAF2017-82886-R SAF2017-82886-R/AEI/10.13039/501100011033 info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2015-64767-R info:eu-repo/grantAgreement/EC/FP7/294340 S2017/BMD-3671/INFLAMUNE-CM info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SEV-2015-0505 http://dx.doi.org/10.1161/CIRCULATIONAHA.118.034326 Sí |
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info:eu-repo/semantics/openAccess |
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openAccess |
| dc.publisher.none.fl_str_mv |
American Heart Association |
| publisher.none.fl_str_mv |
American Heart Association |
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reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC instname:Consejo Superior de Investigaciones Científicas (CSIC) |
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Consejo Superior de Investigaciones Científicas (CSIC) |
| reponame_str |
DIGITAL.CSIC. Repositorio Institucional del CSIC |
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DIGITAL.CSIC. Repositorio Institucional del CSIC |
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1869407363634561024 |
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Oxidized Low-Density Lipoprotein Receptor in Lymphocytes Prevents Atherosclerosis and Predicts Subclinical DiseaseTsilingiri, KaterinaFuente, Hortensia de laRelaño, MartaSánchez-Díaz, RaquelRodríguez-Sinovas, CristinaCrespo, JavierSánchez-Cabo, FátimaDopazo, AnaAlonso-Lebrero, José LuisVara, AliciaVázquez, JesúsCasasnovas, José MaríaAlfonso, FernandoIbáñez, BorjaFuster, ValentínMartínez-González, JoséMartín, PilarSánchez-Madrid, FranciscoAtherosclerosisCD69 antigenOxidized low density lipoproteinRegulatory TLymphocytesTh17 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.Funding was provided by the Spanish Ministry of Economy and Competitiveness: Plan Nacional de Salud SAF2017-82886-R to Dr Sánchez-Madrid, SAF2015-64767-R to Dr Martínez-González; Instituto de Salud Carlos III (AES 2016): PI16/01956 to Dr Martin, Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares; European Research Council, ERC-2011-AdG294340-GENTRIS to Dr Sánchez-Madrid; Proyecto Integrado de Excelencia PIE13/041 and Fundació La Marató TV3 (20152330 31); and Comunidad Autónoma de Madrid CAM (S2017/BMD-3671) to Drs Martin and Sánchez-Madrid. Dr Tsilingiri is cofunded by the European Union Marie Curie Program. M. Relaño is supported by a Contratos Predoctorales Severo Ochoa para la formación de doctores (BES-2015–072625) from the Spanish Ministry of Economy and Competitiveness. This research has been cofinanced by Fondo Europeo de Desarrollo Regional. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain, is supported by the Ministerio de Ciencia, Innovación y Universidades, and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505). The PESA study is cofunded equally by the Pro CNIC Foundation and Banco Santander, Madrid, Spain.American Heart AssociationAgencia Estatal de Investigación (España)Ministerio de Economía y Competitividad (España)Ministerio de Ciencia, Innovación y Universidades (España)Instituto de Salud Carlos IIIRed Temática de Investigación Cooperativa en Enfermedades Cardiovasculares (España)European Research CouncilFundació La Marató de TV3Comunidad de MadridEuropean CommissionCentro Nacional de Investigaciones Cardiovasculares (España)Fundación Pro CNICBanco SantanderConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2020202020192020info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/201708reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/SAF2017-82886-RSAF2017-82886-R/AEI/10.13039/501100011033info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2015-64767-Rinfo:eu-repo/grantAgreement/EC/FP7/294340S2017/BMD-3671/INFLAMUNE-CMinfo:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SEV-2015-0505http://dx.doi.org/10.1161/CIRCULATIONAHA.118.034326Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2017082026-05-22T06:33:51Z |
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15,811543 |