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Investigating mechanisms of oxidized phospholipid-mediated dysregulation of regulatory T cells in atherosclerosis

研究动脉粥样硬化中氧化磷脂介导的调节性 T 细胞失调的机制

基本信息

批准号：
10648711
负责人：
AMY S MAJOR
金额：
$ 26.25万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-03 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10648711
关键词：
Affect Animal Model Arterial Fatty Streak Arteries Atherosclerosis C57BL/6 Mouse CD36 gene CD4 Positive T Lymphocytes Cardiac Cardiovascular Diseases Cause of Death Cell Compartmentation Cell Count Cell Fraction Cell Survival Cell physiology Cells Cellular biology Cholesterol Clinical Data Disease Outcome Endothelial Cells Environment Event FOXP3 gene Feedback Functional disorder Funding Mechanisms Future Growth Human Hyperlipidemia Immune In Vitro Inflammatory Interferons Intervention Knockout Mice Laboratories Lesion Lipids Macrophage Measures Mediating Myocardial Infarction Nature Pathogenicity Patients Phenotype Phospholipids Play Population Process Production Proteins Receptor Signaling Regulatory T-Lymphocyte Research Role Rupture Signal Transduction T cell differentiation T-Lymphocyte T-bet protein TLR4 gene Testing United States Work adaptive immunity atherogenesis cell dedifferentiation cytokine effector T cell experimental study in vivo insight lipid metabolism mouse model novel oxidized low density lipoprotein oxidized phosphatidyl choline receptor response scavenger receptor single-cell RNA sequencing tumor microenvironment uptake

项目摘要

SUMMARY The important role of adaptive immunity in cardiovascular disease (CVD) is established. However, much is still unknown regarding how adaptive immunity can be manipulated to benefit CVD outcomes. Atherosclerosis, the most common form of CVD, is characterized by accumulation of lipid and immune cells in the artery wall that leads to plaque formation. Recent single cell RNAseq data in human atherosclerotic confirm that T cells make up a large fraction of the cell population in lesions. T cells are important to the atherosclerotic process as effector T cells (Th1 and Th17) seem to promote plaque growth and instability whereas regulatory T cells (Tregs) are critical for inhibition of atherogenesis and induce regression of established plaques. In humans, Tregs are associated with plaque stability and protection against cardiac events. These data are consistent with mouse models that show Tregs numbers in plaques decrease as atherosclerosis progresses and remaining Tregs Th1-like inflammatory phenotype. Why Tregs dedifferentiate or become dysfunctional in atherosclerosis is not completely understood, but recent studies suggest that oxidized low density lipoprotein (oxLDL) may play a functional role in this process. Preliminary studies from our laboratory examined whether oxidized phospholipid (oxPAPC), associated with atherosclerosis and oxLDL, could affect Treg differentiation, stability, and function. Our preliminary data show that, oxPAPC reduced Treg viability and increased expression of the Th1-associated transcription factor T-bet and production of IFN- thus promoting the Th1-like Treg phenotype. This effect was Treg-specific as cells skewed in Th1 or Th17 conditions were not affected by oxPAPC. These oxPAPC Tregs were also less suppressive in vitro. The effect of oxPAPC on Tregs was partially dependent on CD36 and IFN-. Interestingly, IFN- has been shown to destabilize Tregs in the tumor microenvironment and data in this proposal show that neutralization of IFN- in Treg skewing cultures inhibits expression of T-bet in FoxP3+ cells. Therefore, we hypothesize that oxidized phospholipids associated with atherosclerosis induce an effector- phenotype in Tregs that is partially dependent on IFN-. To test this hypothesis we propose two specific aims. The first will examine the role of CD36/TLR and IFN- signaling on the dysregulation of Tregs in the presence of oxPLs and determine if these Tregs can protect from atherosclerosis in vivo. The second, will examine whether CD36 or responses to IFN- are responsible for destabilization of the Treg compartment during atherosclerosis in vivo. This work will uncover novel information on the role of oxidized phospholipid on Treg dysfunction in atherosclerosis and will provide valuable insight for future clinical interventions.

总结