2024-03-29T05:13:56Zhttp://repisalud.isciii.es/oai/requestoai:repisalud.isciii.es:20.500.12105/70162023-04-19T12:35:59Zcom_20.500.12105_2145com_20.500.12105_2051com_20.500.12105_2144col_20.500.12105_2146
00925njm 22002777a 4500
dc
Tsilingiri, Katerina
author
de la Fuente, Hortensia
author
Relano, Marta
author
Sanchez-Diaz, Raquel
author
Rodriguez, Cristina
author
Crespo, Javier
author
Sanchez-Cabo, Fatima
author
Dopazo, Ana
author
Alonso-Lebrero, José L
author
Vara, Alicia
author
Vazquez, Jesus
author
Casasnovas, José M
author
Alfonso, Fernando
author
Ibáñez, Borja
author
Fuster, Valentin
author
Martinez-Gonzalez, Jose
author
Martin, Pilar
author
Sanchez-Madrid, Francisco
author
2019-01-08
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.
Circulation. 2019; 139(2):243-255
0009-7322
http://hdl.handle.net/20.500.12105/7016
30586697
10.1161/CIRCULATIONAHA.118.034326
1524-4539
Circulation
CD69 antigen
Th17 cells
Atherosclerosis
Oxidized low density lipoprotein
Regulatory T lymphocytes
Oxidized Low-Density Lipoprotein Receptor in Lymphocytes Prevents Atherosclerosis and Predicts Subclinical Disease