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.

摘要 获得性免疫在心血管疾病(CVD)中的重要作用被确立。然而，很多事情仍然是 尚不清楚适应性免疫如何被操纵以有利于心血管疾病的结果。动脉粥样硬化， 最常见的CVD的特征是动脉壁中脂质和免疫细胞的积聚， 会导致斑块的形成。最近在人类动脉粥样硬化中的单细胞RNAseq数据证实，T细胞使 在病变中增加了很大一部分细胞。T细胞在动脉粥样硬化过程中非常重要，因为 效应T细胞(Th1和Th17)似乎促进斑块的生长和不稳定，而调节性T细胞 (Tregs)对于抑制动脉粥样硬化形成和诱导已建立的斑块消退至关重要。在人类中，Tregs 与斑块稳定性和预防心脏事件有关。这些数据与 斑块中Tregs数量随着动脉粥样硬化的进展而减少的小鼠模型以及剩余的Tregs数量 Th1样炎性表型。为什么Tregs在动脉粥样硬化中去分化或功能障碍 完全理解，但最近的研究表明，氧化型低密度脂蛋白(OxLDL)可能在 在这一过程中的职能作用。我们实验室的初步研究检测了氧化磷脂 (OxPAPC)与动脉粥样硬化和oxLDL相关，可影响Treg的分化、稳定性和功能。 我们的初步数据显示，oxPAPC降低了Treg的活性，增加了Th1相关细胞的表达 转录因子T-bet和干扰素-的产生，从而促进Th1型Treg表型。这种影响是 在Th1或Th17条件下倾斜的Treg特异性AS细胞不受oxPAPC的影响。这些oxPAPC树 在体外也不那么受抑制。OxPAPC对Treg的作用部分依赖于CD36和干扰素-。 有趣的是，在这项提案中，干扰素-已经被证明可以破坏肿瘤微环境和数据中Treg的稳定。 结果表明，在Treg偏斜培养中中和干扰素-可以抑制FoxP3+细胞中T-bet的表达。因此， 我们假设与动脉粥样硬化相关的氧化磷脂诱导了一个效应器- Tregs的表型部分依赖于干扰素-。为了检验这一假设，我们提出了两个具体的 目标。第一个将研究CD36/TLR和干扰素-信号在Tregs异常调节中的作用。 是否存在oxPLs，并确定这些Tregs是否可以在体内保护动脉粥样硬化。第二，威尔 检查CD36或对干扰素-的反应是否导致Treg间隔室的不稳定 在体内动脉粥样硬化的过程中。这项工作将揭示氧化磷脂在人体内的作用。 Treg在动脉粥样硬化中的功能障碍，将为未来的临床干预提供有价值的见解。