Atherosclerosis is a disease characterized by the accumulation of lipid deposits in the artery wall, but the disease is usually not detected until after it has caused a clinical event such as a myocardial infarction or stroke. Cardiovascular disease is the single largest cause of death in the world, and preventive strategies for this disease are therefore a major priority. Because of the diminished quality of life experienced by affected individuals, treatment after symptoms appear is of limited benefit, and the long-term management of the disease is a major cost for health care systems. The origin of atherosclerosis and its progression to acute myocardial infarction and stroke involve an essential contribution from the inflammatory immune response. Earlier detection of cardiovascular disease is a step closer thanks to the findings of a research team at the Centro Nacional de Investigaciones Cardiovasculares (CNIC) led by doctors Francisco Sánchez-Madrid and Pilar Martín. However, according to a team of the Hospital Universitario de la Princesa (Madrid), the relationship between lipid metabolism and the immune response is not well understood.
The study identifies the molecule CD69 as a T cell receptor for oxidized lipoproteins that contributes to the control of inflammation and thus prevents the development of atherosclerosis. 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. The team 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. The established hypothesis is that oxidized low-density lipoproteins (LDLox) induce the recruitment of inflammatory immune cells and their accumulation in the plaque; however, there is also evidence that cells and tissues can respond to LDLox by inhibiting pro-inflammatory signals. Therefore, one might speculate that unhealthy diet might harm vascular health through an immune-mediated mechanism. The scientists have found that the expression level of the molecule CD69 in blood cells inversely predicts the appearance of subclinical atherosclerosis (developing before symptoms appear) independently of classical cardiovascular disease.
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 lymphocytes were performed to decipher the mechanism of the observed phenotypes. Scientists measured the expression of CD69 and NR4A nuclear receptors by reverse transcription-polymerase chain reaction. NR4 receptors are a group of orphans proteins involved in the development and maturation of immune cells. So far they encompass Nur77 (NR4A1), Nurr1 (NR4A2) and NOR1 (NR4A3). Binding of LDLox to CD69 triggers the adoption of an anti-inflammatory profile by T lymphocytes that protects against the development of atherosclerosis in mice and humans. For this research project, the team used mice lacking the CD69 gene. 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. LDLox was shown to bind specifically to CD69 on human T lymphocytes, inhibiting the development of Th17 cells. Downstream mechanism of this phenomenon was the activation of NR4A receptors, which couple with a specific pattern of gene expression.
The clinical relevance of the study is demonstrated by the results of an analysis of immune CD69 in blood samples obtained from 305 participants in the PESA project (Progression of Early Subclinical Atherosclerosis). PESA is a prospective study that uses advanced imaging techniques to detect the presence of atherosclerotic plaques in overtly healthy individuals. Participants of the PESA study with evidence of subclinical atherosclerosis displayed a significant CD69 and NR4A1 mRNA down-regulation in peripheral blood white cells compared with asymptomatic participants. The expression of CD69 remained associated with the risk of subclinical atherosclerosis. This part of the study was conducted in partnership with the PESA project investigators Valentín Fuster and Borja Ibáñez and the CNIC technical units focused on Bioinformatics, Genomics and Proteomics. The results of the study show that the expression of CD69 in circulating lymphocytes correlates inversely with the presence and extent of subclinical atherosclerosis. For the clinical impact of the data, the whole research has been published in the AHA journal Circulation.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry
Tsilingiri K et al. Circulation 2019; 139(2):243-255.
Brait VH et al., Planas AM. Circ Res. 2018 Dec 3.
Cibrian D et al. Eur J Immunol. 2017; 47(6):946-953.