The development and rupture of atherosclerotic plaques is a major contributor to myocardial infarctions and ischemic strokes. The dynamic evolution of the plaque is largely attributed to monocyte/macrophage functions, which respond to various stimuli in the plaque microenvironment. To this end, macrophages play a central role in atherosclerotic lesions through the uptake of oxidized low-density lipoprotein that gets trapped in the artery wall, and the induction of an inflammatory response that can differentially affect the stability of the plaque in men and women. In this environment, macrophages can polarize towards pro-inflammatory M1 or anti-inflammatory M2 phenotypes, which represent the extremes of the polarization spectrum that include Mhem, M(Hb), Mox, and M4 populations. However, this traditional macrophage model paradigm has been redefined to include numerous immune and nonimmune cell clusters based on in-depth unbiased single-cell approaches. The goal of this review is to highlight (1) the phenotypic and functional properties of monocyte subsets in the circulation, and macrophage populations in atherosclerotic plaques, as well as their contribution towards stable or unstable phenotypes in men and women, and (2) single-cell RNA sequencing studies that have advanced our knowledge of immune, particularly macrophage signatures present in the atherosclerotic niche. We discuss the importance of performing high-dimensional approaches to facilitate the development of novel sex-specific immunotherapies that aim to reduce the risk of cardiovascular events.

摘要

动脉粥样硬化斑块的形成和破裂是心肌梗塞和缺血性中风的主要原因。斑块的动态演化很大程度上归因于单核细胞/巨噬细胞功能，它们对斑块微环境中的各种刺激做出反应。为此，巨噬细胞通过摄取被困在动脉壁中的氧化低密度脂蛋白，并诱导炎症反应，从而对男性和女性斑块的稳定性产生不同的影响，从而在动脉粥样硬化病变中发挥核心作用。在这种环境中，巨噬细胞可以极化为促炎 M1 或抗炎 M2 表型，这代表了极化谱的极端，包括 Mhem、M(Hb)、Mox 和 M4 群体。然而，这种传统的巨噬细胞模型范式已被重新定义，以包括基于深入无偏单细胞方法的大量免疫和非免疫细胞簇。本综述的目的是强调（1）循环中单核细胞亚群和动脉粥样硬化斑块中巨噬细胞群的表型和功能特性，以及它们对男性和女性稳定或不稳定表型的贡献，以及（2）单一-细胞RNA测序研究提高了我们对免疫的认识，特别是动脉粥样硬化微环境中存在的巨噬细胞特征。我们讨论了进行高维方法以促进新型性别特异性免疫疗法的开发的重要性，这些免疫疗法旨在降低心血管事件的风险。