The role of mitochondrial metabolism in T cell activation by particulate matter

描述(由申请人提供)：暴露在颗粒性空气污染中会减少预期寿命，并可能导致哮喘、过敏以及肺部和心血管疾病发病率的增加。吸入颗粒物(PM)会引起呼吸道高反应性、细胞炎症和粘液分泌，这些似乎在很大程度上是由激活的T细胞介导的。当T细胞被激活时，它们会启动一个促进生存和快速增殖的程序。从静息状态到高度增殖状态的这种转换需要细胞新陈代谢的重大变化。目前关于T细胞代谢的教条是，幼稚的静止T细胞依赖线粒体代谢，激活的T细胞依赖糖酵解代谢，然而目前的项目将挑战这一教条。在许多增殖细胞中，糖酵解可能是通往戊糖磷酸途径的重要通道，但它不足以提供增殖所需的全部因子。线粒体代谢需要通过TCA循环产生柠檬酸，以制造膜合成所需的脂类。此外，已有研究表明，线粒体ROS是促进细胞周期进程所必需的。目前的提议将利用T细胞中线粒体代谢基因有条件地缺失的小鼠来阐明线粒体代谢在T细胞激活中的作用。我们将挑战这些暴露于PM的小鼠，看看抑制线粒体代谢是否可以减少T细胞介导的炎症。这项研究的结果可能从根本上改变目前T细胞代谢的概念，以及提供可能受到药物制剂控制的代谢和信号靶点。 公共卫生相关性：吸入颗粒物(PM)可诱导T细胞介导的炎症，并与哮喘、过敏、肺和心血管疾病的发病率增加相关。这个项目将评估线粒体代谢在T细胞激活中的作用，并使用PM暴露作为一个模型来确定T细胞介导的炎症的代谢需求。重要的是，这项工作将定义代谢和信号通路，这些通路可以被药物调节，以抑制T细胞对PM或其他良性抗原的反应。

DESCRIPTION (provided by applicant): Exposure to particulate air pollution reduces life expectancy and likely contributes to the increased incidence of asthma, allergy, and pulmonary and cardiovascular disease. Inhalation of particulate matter (PM) causes airway hyperresponsiveness, cellular inflammation, and mucus secretion, which appear to be mediated in large part by activated T cells. When T cells are activated, they initiate a program that promotes survival and initiates rapid proliferation. This switch from a resting state to a highly proliferative state requires substantial alterations in cell metabolism. The current dogma of T cell metabolism is that naive resting T cells rely on mitochondrial metabolism and activated T cells rely on glycolytic metabolism, however the current project will challenge this dogma. In many proliferating cells, glycolysis may be important as a conduit to the pentose phosphate pathway, but it is insufficient to provide the full complement of factors needed for proliferation. Mitochondrial metabolism is needed to produce citrate through the TCA cycle to make lipids for membrane synthesis. Furthermore, it has been shown that mitochondrial ROS are required to promote cell cycle progression. The current proposal will utilize mice that have mitochondrial metabolic genes conditionally deleted in T cells to elucidate the role of mitochondrial metabolism in T cell activation. We will challenge these mice with PM exposure to see if inhibition of mitochondrial metabolism could reduce T cell-mediated inflammation. The results of this study could fundamentally change the current conception of T cell metabolism, as well as provide metabolic and signaling targets that could be subject to control by pharmaceutical agents. PUBLIC HEALTH RELEVANCE: Inhalation of particulate matter (PM) induces T cell-mediated inflammation and correlates with increased incidence of asthma, allergy, and pulmonary and cardiovascular disease. This project will assess the role of mitochondrial metabolism in T cell activation and use PM exposure as a model to determine metabolic requirements of T cell-mediated inflammation. Importantly, this work will define metabolic and signaling pathways that could be modulated by pharmaceutical agents to dampen the T cell response to PM or other benign antigens.