BACKGROUND Monocytes are a critical innate immune system cell type that serves homeostatic and immunoregulatory functions. They have been identified historically by the cell surface expression of CD14 and CD16. However, recent single-cell studies have revealed that they are much more heterogeneous than previously realized. METHODS We utilized cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) and single-cell RNA sequencing to describe the comprehensive transcriptional and phenotypic landscape of 437 126 monocytes. RESULTS This high-dimensional multimodal approach identified vast phenotypic diversity and functionally distinct subsets, including IFN-responsive, MHCIIhi (major histocompatibility complex class II), monocyte-platelet aggregates, as well as nonclassical, and several subpopulations of classical monocytes. Using flow cytometry, we validated the existence of MHCII+CD275+ MHCIIhi, CD42b+ monocyte-platelet aggregates, CD16+CD99- nonclassical monocytes, and CD99+ classical monocytes. Each subpopulation exhibited unique characteristics, developmental trajectories, transcriptional regulation, and tissue distribution. In addition, alterations associated with cardiovascular disease risk factors, including race, smoking, and hyperlipidemia were identified. Moreover, the effect of hyperlipidemia was recapitulated in mouse models of elevated cholesterol. CONCLUSIONS This integrative and cross-species comparative analysis provides a new perspective on the comparison of alterations in monocytes in pathological conditions and offers insights into monocyte-driven mechanisms in cardiovascular disease and the potential for monocyte subpopulation targeted therapies.

中文翻译：

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心血管疾病风险状态下的单核细胞单细胞多模式分析。


背景 单核细胞是一种关键的先天免疫系统细胞类型，具有稳态和免疫调节功能。历史上，它们是通过 CD14 和 CD16 的细胞表面表达来识别的。然而，最近的单细胞研究表明，它们的异质性比以前意识到的要大得多。方法 我们利用通过测序对转录组和表位进行细胞索引 （CITE-seq） 和单细胞 RNA 测序来描述 437 126 个单核细胞的综合转录和表型景观。结果这种高维多模式方法确定了巨大的表型多样性和功能不同的亚群，包括 IFN 反应、MHCIIhi （主要组织相容性复合体 II 类）、单核细胞-血小板聚集体，以及非经典和经典单核细胞的几个亚群。使用流式细胞术，我们验证了 MHCII+CD275+MHCIIhi、CD42b+单核细胞-血小板聚集体、CD16+CD99-非经典单核细胞和 CD99+经典单核细胞的存在。每个亚群都表现出独特的特征、发育轨迹、转录调控和组织分布。此外，还确定了与心血管疾病危险因素相关的改变，包括种族、吸烟和高脂血症。此外，高脂血症的影响在胆固醇升高的小鼠模型中进行了概括。结论 这种综合和跨物种的比较分析为病理条件下单核细胞改变的比较提供了新的视角，并提供了对心血管疾病中单核细胞驱动机制和单核细胞亚群靶向治疗潜力的见解。