Migratory and Dancing Macrophage Subsets in Atherosclerotic Lesions
Migratory and Dancing Macrophage Subsets in Atherosclerotic Lesions
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DOI：
10.1161/circresaha.119.315175
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发表时间：
2019-12-06
影响因子：
20.1
通讯作者：
Ley, Klaus
中科院分区：
文献类型：
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作者：
McArdle, Sara;Buscher, Konrad;Ley, Klaus
理由：巨噬细胞是动脉粥样硬化的重要调节因子。它们分泌细胞因子，加工脂蛋白和胆固醇，并吸收凋亡细胞。斑块巨噬细胞存在多种亚群，并且它们的不同作用正在出现。 目的：在这里，我们使用转基因荧光小鼠探索动脉粥样硬化斑块中巨噬细胞的异质性，其中巨噬细胞亚群被 GFP（绿色荧光蛋白）、YFP（黄色荧光蛋白）标记，或者两者都不标记。目的是定义可见亚群的迁移模式并将其与其表型和转录组相关联。方法和结果：Apoe(-/-) Cx3cr1(GFP) Cd11c(YFP) 小鼠的主动脉中有 4 组巨噬细胞。 3 个可见子集显示出不同的运动特征。 GFP 和 GFP+YFP+ 巨噬细胞延伸和缩回树突状突起，在现场跳舞，几乎没有净运动，而 YFP 巨噬细胞具有更圆形的形状并沿着动脉迁移。分选细胞的 RNA 测序揭示了由 GFP 和 YFP 表达定义的 4 个子集的基因表达模式存在显着差异，特别是在趋化因子和细胞因子表达、基质重塑和细胞形状动力学方面。基因集富集分析显示，GFP+细胞与在具有三级淋巴器官和消退斑块的动脉中发现的细胞具有相似的转录组，而YFP+细胞与进展和稳定斑块相关。结论：定量活体成像与深层转录组的结合鉴定了动脉粥样硬化中具有独特转录组谱的4个血管巨噬细胞亚群。我们的数据将血管巨噬细胞转录组与其体内迁移功能联系起来。未来需要研究基因表达和运动特征变化的功能意义，以充分了解这些子集如何促进疾病进展。
Rationale: Macrophages are essential regulators of atherosclerosis. They secrete cytokines, process lipoproteins and cholesterol, and take up apoptotic cells. Multiple subsets of plaque macrophages exist and their differential roles are emerging.Objective: Here, we explore macrophage heterogeneity in atherosclerosis plaques using transgenic fluorescent mice in which subsets of macrophages are labeled by GFP (green fluorescent protein), YFP (yellow fluorescent protein), neither, or both. The objective was to define migration patterns of the visible subsets and relate them to their phenotypes and transcriptomes.Methods and Results: Apoe(-/-) Cx3cr1(GFP) Cd11c(YFP) mice have 4 groups of macrophages in their aortas. The 3 visible subsets show varying movement characteristics. GFP and GFP+YFP+ macrophages extend and retract dendritic processes, dancing on the spot with little net movement while YFP macrophages have a more rounded shape and migrate along the arteries. RNA sequencing of sorted cells revealed significant differences in the gene expression patterns of the 4 subsets defined by GFP and YFP expression, especially concerning chemokine and cytokine expression, matrix remodeling, and cell shape dynamics. Gene set enrichment analysis showed that GFP+ cells have similar transcriptomes to cells found in arteries with tertiary lymphoid organs and regressing plaques while YFP+ cells were associated with progressing and stable plaques.Conclusions: The combination of quantitative intravital imaging with deep transcriptomes identified 4 subsets of vascular macrophages in atherosclerosis that have unique transcriptomic profiles. Our data link vascular macrophage transcriptomes to their in vivo migratory function. Future work on the functional significance of the change in gene expression and motility characteristics will be needed to fully understand how these subsets contribute to disease progression.