The role of Trem2-expressing macrophages in atherosclerosis

项目总结

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.