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 在此PPG的最后一个周期中，我们使用了使用的八个使用 高维质量细胞仪。这些子集现已在其他研究中得到证实。我们 发现某些单核细胞子集表达四叠蛋白酶CD9，并且这些CD9+单核细胞 子集与人类的心血管疾病（CAD）严重程度呈正相关。四翼胺 CD9促进了膜内受体的组织和聚类。 CD9调节MHCII 在髓样细胞中运输对T细胞的激活至关重要，有助于巨噬细胞吸收OXLDL 通过组织清道夫受体CD36的质膜聚类。因此，CD9位于 膜允许调节免疫受体活性。功能途径分析 CD9+单核细胞揭示了与炎症，白细胞迁移和 补体激活途径。尽管这种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，我们推测这些功能 功能可能在容器壁上变得有害，并促进动脉粥样硬化。我们也是 最近有证据表明，CD9+单核细胞在主动脉壁中产生CD9+巨噬细胞。 在这里，我们假设免疫调节CD9+单核细胞和CD9+巨噬细胞促进 动脉粥样硬化进展通过促进促炎性细胞因子程序，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。 我们将在两个特定目标中检验该假设 动脉粥样硬化的模型。 AIM 1将在人类受试者中功能研究CD9+单核细胞子集 临床记录的低和高CAD以及受试者的临床文献良好的临床队列 参加牙菌斑进展的纵向研究的人。 AIM 2将机械地研究 CD9+巨噬细胞子集的功能和代谢，将直接测试单核细胞和 巨噬细胞CD9在调节动脉粥样硬化进程中的表达。我们将利用独特的单核细胞 - 特定的小鼠模型（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 （CCR2 - / - ）在功能上检查经典或非经典单核细胞中的CD9如何调节 动脉粥样硬化的发展。这些完成的目标在一起，可能会导致新的目标 生物标志物和用于动脉粥样硬化单核细胞免疫调节的疗法。