The role of Trem2-expressing macrophages in atherosclerosis

项目摘要 巨噬细胞是动脉粥样硬化脂质斑块中的中心炎性细胞类型。但 巨噬细胞表型对斑块形成的影响仍不清楚。我们实验室的工作 最近描述了一个组织巨噬细胞亚群，其出现在与细胞外脂质相关的环境中， 积累这些巨噬细胞被称为脂质相关巨噬细胞（LAMs）的基础上， 通过单细胞分析和细胞外脂质周围定位的基因表达谱。LAM的特征在于 通过表达单跨膜蛋白Trem 2，既作为一种标志物，又作为一种重要的驱动因素， LAM世代。我们的研究结果表明，Trem 2驱动参与脂质代谢的基因的表达。 此外，已发现Trem 2可作为脂质和脂蛋白的传感器。因此，Trem 2可以用作 细胞外脂质积累信号的模式识别受体，这反过来又驱动一个保守的 免疫应答旨在减少疾病如动脉粥样硬化中细胞外脂质的负担。 然而，Trem 2表达巨噬细胞在动脉粥样硬化中的作用仍然未知。此外该 诱导Trem 2表达的分子机制是未知的。因此，这一提议的核心假设 Trem 2驱动巨噬细胞的组织特异性表达谱， 这是细胞外脂质积累的信号，这种巨噬细胞亚群的功能是减少细胞内脂质的积累。 动脉粥样硬化中脂质的病理性积聚。为了检验这一假设，提出了两个具体目标： 目的1通过比较动脉粥样硬化负荷和免疫细胞的变化，探讨Trem 2在动脉粥样硬化中的作用 在遗传上缺乏Trem 2的小鼠及其同窝对照的动脉粥样硬化斑块中， 动脉粥样硬化Ldlr-/-和Apoe-/-模型。在目标2中，Trem 2表达的诱导剂将使用免疫组织化学方法鉴定。 新型Trem 2报告小鼠，与体外巨噬细胞培养物和治疗条件组合。我有 我已经生成了解决我的具体目标所需的工具箱，包括遗传模型和初步的 数据总之，这些研究的完成将从根本上推进我们对一种新的 在组织代谢失调的背景下发现免疫反应，并开拓可操作的目标 由此可以通过疾病中的免疫疗法来调节组织生理学。此外，这项工作符合我的 培训目标，让我使用尖端的实验，计算和概念工具，在 最前沿的一个跨学科领域连接免疫学和代谢，开始我的职业生涯在学术界。

PROJECT SUMMARY Macrophages are the central inflammatory cell types in atherosclerotic lipid-laden plaques. However, the influence of macrophage phenotype on the development of plaques remains unclear. Work from our lab has recently described a subset of tissue macrophages that appears in contexts associated with extracellular lipid accumulation. These macrophages were termed Lipid-Associated Macrophages (LAMs) on the basis of their gene expression profile by single cell profiling and localization around extracellular lipids. LAMs are characterized by the expression of the single transmembrane protein Trem2, both as a marker and as an essential driver of LAM generation. Our findings suggest that Trem2 drives the expression of genes involved in lipid metabolism. In addition, Trem2 has been found to act as a sensor for lipids and lipoproteins. Thus, Trem2 may function as a pattern-recognition receptor for signals of extracellular lipid accumulation, which in turn drives a conserved immune response aimed to reduce the burden of extracellular lipid in a disease such as atherosclerosis. However, the role of Trem2-expressing macrophages in atherosclerosis remains unknown. In addition, the molecular mechanisms that induce Trem2 expression are unknown. Thus, the central hypothesis of this proposal is that Trem2 drives a tissue-specialized expression profile of macrophages that can be induced in response to a signal of extracellular lipid accumulation, and the function of this macrophage subset is to reduce the pathological accumulation of lipid in atherosclerosis. To test this hypothesis, two specific aims are proposed: Aim 1 is to determine the role of Trem2 in atherosclerosis by comparing atherosclerotic burden and immune cell phenotypes in atherosclerotic plaques of mice genetically lacking Trem2 and their littermate controls using both the Ldlr-/- and Apoe-/- model of atherosclerosis. In Aim 2, inducers of Trem2 expression will be identified using a novel Trem2 reporter mouse, combined with in vitro macrophage cultures and treatment conditions. I have already generated the toolbox needed to address my specific aims, including genetic models and preliminary data. Taken together, the completion of these studies will fundamentally advance our knowledge of a newly discovered immune response in the context of tissue metabolic dysregulation, and pioneer actionable targets whereby tissue physiology can be modulated by immunotherapy in disease. In addition, this work aligns with my training goals by allowing me to use cutting-edge experimental, computational, and conceptual tools at the forefront of an interdisciplinary field linking immunology and metabolism, to initiate my career in academia.