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

• 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
• 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

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.

概括 适应性免疫学在心血管疾病（CVD）中的重要作用得以建立。但是，还有很多 关于如何操纵自适应免疫以使CVD结果受益的未知。动脉粥样硬化， CVD的最常见形式的特征是脂质和免疫细胞在动脉壁中积累 导致牙菌斑形成。人动脉粥样硬化中最近的单细胞RNASEQ数据证实T细胞使得 在病变中增加大部分细胞群。 T细胞对动脉粥样硬化过程很重要 效应T细胞（Th1和Th17）似乎促进了斑块的生长和不稳定性，而调节性T细胞 （Treg）对于抑制动脉粥样硬化和诱导已建立斑块的回归至关重要。在人类中 与斑块稳定性和防止心脏事件有关。这些数据与 随着动脉粥样硬化的进展和剩余的Treg，显示斑块中Tregs数字的小鼠模型减少 Th1样炎症表型。为什么tregs在动脉粥样硬化中去分化或变得功能失调不是 完全理解，但最近的研究表明，氧化的低密度脂蛋白（OXLDL）可能会发挥作用 在此过程中的功能作用。我们实验室的初步研究检查了是否氧化了磷脂 （OXPAPC）与动脉粥样硬化和OXLDL有关，可能会影响Treg的分化，稳定性和功能。 我们的初步数据表明，OXPAPC降低了Treg生存力，并增加了与Th1相关的表达 转录因子T-bet和IFN-的产生，从而促进了Th1样Treg表型。这种效果是 Treg特异性作为在Th1或Th17条件下偏斜的细胞不受OXPAPC的影响。这些OXPAPC Tregs 体外也不那么抑制。 OXPAPC对Tregs的影响部分取决于CD36和IFN-。 有趣的是，IFN-已被证明会破坏肿瘤微环境中的Treg和该提案中的数据 表明Treg偏斜培养物中IFN-的中和抑制了Foxp3+细胞中T-bet的表达。所以， 我们假设与动脉粥样硬化相关的氧化磷脂会引起效应 - Treg中的表型部分取决于IFN-。为了检验这一假设，我们提出了两个特定的 目标。第一个将检查CD36/TLR和IFN-信号传导在Tregs中的作用 OXPLS的存在，并确定这些Treg是否可以在体内保护动脉粥样硬化。第二，威尔 检查CD36还是对IFN-的响应是导致Treg隔室不稳定的 在体内动脉粥样硬化期间。这项工作将发现有关氧化磷脂在作用的新信息 动脉粥样硬化中的Treg功能障碍，将为将来的临床干预提供宝贵的见解。