Project 1: Regulation of CD9+ Monocyte & Macrophage Immune Functions in Atherosclerosis

项目1：CD9单核细胞的调控

• 批准号: 10334094
• 负责人: Catherine C Hedrick
• 金额: $ 4.33万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-06-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10334094
• 关键词: Angiography; Anti-Inflammatory Agents; Antigens; Aorta; Arterial Fatty Streak; Atherosclerosis; Automobile Driving; B-Lymphocytes; Back; Biological Markers; Blood; Blood Vessels; Body Weight; Body mass index; CD14 gene; CD36 gene; Cardiovascular Diseases; Cause of Death; Cell Communication; Cell membrane; Cell physiology; Cells; Characteristics; Clinical; Complement Activation; Coronary; Cytometry; Development; Disease Progression; Disease model; FCGR3B gene; Frequencies; Funding; Gene Expression Profile; Glycosylated hemoglobin A; Homeostasis; Human; Hybrids; IL1B gene; Immune; Immunologic Receptors; Individual; Inflammation; Inflammatory; Knowledge; Lead; Leukocytes; Link; Lipids; Location; Longitudinal Studies; Membrane; Membrane Lipids; Membrane Proteins; Metabolic; Metabolism; Multi-Ethnic Study of Atherosclerosis; Mus; Myelogenous; Myeloid Cells; Myocardial Infarction; Pathway Analysis; Pathway interactions; Phenotype; Play; Population; Process; Quantitative Trait Loci; Regulation; Role; Severity of illness; Shapes; T-Cell Activation; T-Lymphocyte; TLR4 gene; TNF gene; Testing; Virginia; Virus; X-Ray Computed Tomography; chemokine; cohort; cytokine; gene induction; high dimensionality; human subject; immune function; immunomodulatory therapies; immunoregulation; lipid metabolism; macrophage; migration; monocyte; mouse model; oxidized low density lipoprotein; programs; protein biomarkers; receptor; scavenger receptor; sex; trafficking; transcriptome sequencing; transcriptomics; tumor; uptake

Project 1 Summary In the last cycle of this PPG, we identified eight subsets of human monocytes in healthy individuals using high dimensional mass cytometry. These subsets have now been confirmed in other studies. We discovered that some monocyte subsets expressed the tetraspanin CD9, and that these CD9+ monocyte subsets positively correlated with cardiovascular disease (CAD) severity in humans. The tetraspanin CD9 facilitates the organization and clustering of receptors within membranes. CD9 regulates MHCII trafficking in myeloid cells, which is critical for T cell activation, and aids in macrophage uptake of oxLDL by organizing plasma membrane clustering of the scavenger receptor CD36. Thus, CD9 location in membranes allows for the modulation of immune receptor activity. Functional pathway analysis of CD9+ monocytes revealed induction of genes involved in inflammation, leukocyte migration, and complement activation pathways. Although such characteristics would be important for the homeostatic functions of monocytes in clearing viruses, tumors, and damaged host cells, we surmise that these functions could instead become deleterious in the vessel wall, and promote atherosclerosis. We also have recent evidence to suggest that CD9+ monocytes give rise to CD9+ macrophages in the aortic wall. Here, we hypothesize that immunomodulatory CD9+ monocytes and CD9+ macrophages promote atherosclerosis progression by driving a pro-inflammatory cytokine program, regulating plaque macrophage lipid content, and interacting with T cells and B cells to drive plaque progression. We will test this hypothesis in two specific aims, where we study both humans with CAD and mouse models of atherosclerosis. Aim 1 will functionally study CD9+ monocyte subsets in human subjects from well-characterized clinical cohorts, who have clinically-documented low and high CAD, and in subjects who are participating in a longitudinal study of plaque progression. Aim 2 will mechanistically study the functions and metabolism of CD9+ macrophage subsets, and will directly test the role of monocyte and macrophage CD9 expression in regulating atherosclerosis progression. We will utilize unique monocyte- specific mouse models (mice lacking nonclassical monocytes (E2)) and mice lacking classical monocytes (Ccr2-/-) to functionally examine how CD9 in either classical or nonclassical monocytes modulates atherosclerosis development. Together, these completed aims in this renewal could lead to new biomarkers and therapies for immunomodulation of monocytes in atherosclerosis.

项目1摘要 在这个PPG的最后一个周期中，我们使用流式细胞术鉴定了健康个体中的8个人类单核细胞亚群。 高维质谱细胞仪这些子集现在已经在其他研究中得到证实。我们 发现一些单核细胞亚群表达四跨膜蛋白CD 9，这些CD 9+单核细胞 亚群与人类心血管疾病（CAD）严重程度呈正相关。四旋蛋白 CD 9促进膜内受体的组织和聚集。CD 9调节MHCII 骨髓细胞的运输对于T细胞活化至关重要，并有助于巨噬细胞吸收oxLDL 通过组织清道夫受体CD 36的质膜簇。因此，CD 9定位在 膜允许调节免疫受体活性。功能通路分析 CD 9+单核细胞显示参与炎症、白细胞迁移和免疫调节的基因的诱导 补体激活途径。尽管这些特征对于体内平衡很重要， 单核细胞在清除病毒、肿瘤和受损宿主细胞中的功能，我们推测这些 相反，这些功能可能在血管壁中变得有害，并促进动脉粥样硬化。我们也 最近有证据表明，CD 9+单核细胞在主动脉壁中产生CD 9+巨噬细胞。 在这里，我们假设免疫调节性CD 9+单核细胞和CD 9+巨噬细胞促进了 通过驱动促炎细胞因子程序，调节斑块， 巨噬细胞脂质含量，并与T细胞和B细胞相互作用以驱动斑块进展。 我们将在两个特定的目标中测试这一假设，我们研究CAD患者和小鼠。 动脉粥样硬化模型。目的1将从功能上研究人类受试者中的CD 9+单核细胞亚群， 具有良好特征的临床队列，具有临床记录的低和高CAD，以及受试者 他们正在参与一项斑块进展的纵向研究。目标2将机械地研究 CD 9+巨噬细胞亚群的功能和代谢，并将直接测试单核细胞的作用， 巨噬细胞CD 9表达在调节动脉粥样硬化进展中的作用。我们将利用独特的单核细胞- 特异性小鼠模型（缺乏非经典单核细胞（E2）的小鼠）和缺乏经典单核细胞的小鼠 （Ccr 2-/-）来功能性地检查经典或非经典单核细胞中的CD 9如何调节 动脉粥样硬化的发展总之，在这次更新中完成的这些目标可能会导致新的 动脉粥样硬化中单核细胞免疫调节的生物标志物和治疗。