In vivo investigation of non-classical monocyte patrolling mechanism

非经典单核细胞巡逻机制的体内研究

• 批准号: 9124682
• 负责人: Paola Marcovecchio
• 金额: $ 3.62万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9124682
• 关键词: Adaptor Signaling Protein; Adherence; Affect; Affinity; Atherosclerosis; Behavior; Binding; Biological Assay; Blood; Blood Circulation; Blood Platelets; Blood Vessels; Blood flow; CCR5 gene; CD36 gene; Cardiovascular Diseases; Cardiovascular system; Carotid Artery Ulcerating Plaque; Cell surface; Cells; Cessation of life; Characteristics; Cholesterol; Chronic; Data; Disease; Endothelial Cells; Endothelium; Exposure to; Fatty acid glycerol esters; Foam Cells; Frequencies; Future; Heart Diseases; High Fat Diet; Human; Immune; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Integrin alpha Chains; Integrin beta Chains; Integrins; Investigation; Knock-out; Leukocyte Trafficking; Ligands; Literature; Low-Density Lipoproteins; Mediating; Modeling; Molecular Conformation; Mus; Necrosis; Pathway interactions; Play; Process; Resolution; Role; SR-B proteins; Selectins; Signal Transduction; Site; Surveys; Testing; Time; Vascular Cell Adhesion Molecule-1; Work; atherogenesis; atheroprotective; cell type; chemokine; cytokine; feeding; in vivo; macrophage; monocyte; novel; oxidized lipid; oxidized low density lipoprotein; prevent; public health relevance; receptor binding; receptor function; scavenger receptor; therapeutic target; uptake; vascular inflammation; western diet

 DESCRIPTION (provided by applicant): Blood monocytes circulate in the periphery as predominantly two subsets: classical and non- classical, or patrolling, monocytes. It has been shown that classical monocytes contribute early on to the process of atherosclerosis by adhering to the vasculature and migrating to the inner layers of the vessel wall, primarily using selectins and integrins, to eventually become foam cells, leading to a chronic inflammatory state within the vascular layers. The endothelial layer of the blood vessel also becomes activated, releasing pro-inflammatory cytokines and chemokines as well as upregulating integrin ligands such as VCAM-1. Non-classical monocytes have been shown to migrate to plaque sites, although they are less frequent than classical monocytes inside the plaque and upregulate different cell surface markers. During steady state, these non-classical monocytes will spend prolonged times crawling non-directionally along the endothelium to survey the vasculature, although more frequently found in smaller vessels than larger vessels. We have found that during atherogenesis, by feeding mice a western diet that is high in fat and cholesterol, there is a significant increase in the patrolling activity of non-classical monocytes. Previous work in our lab has suggested that these monocytes are atheroprotective, as their absence leads to increases in plaque size and inflammatory monocyte numbers. The function of these non-classical monocytes in atherosclerosis, and the exact mechanism of patrolling, is still unclear, but by studying how non-classical monocytes are activated by this disease, we may be able to elucidate a novel target for treating vascular inflammation and plaque formation.

 描述(申请人提供)：血液单核细胞主要以两个亚群在外周循环：经典和非经典单核细胞，或巡逻单核细胞。已有研究表明，经典单核细胞在动脉粥样硬化的早期过程中，主要利用选择素和整合素，通过黏附于血管系统并迁移到血管内层，最终成为泡沫细胞，导致血管层内的慢性炎症状态。血管内皮层也被激活，释放促炎细胞因子和趋化因子，以及上调整合素配体，如VCAM-1。非经典单核细胞已被证明迁移到斑块部位，尽管它们在斑块内的频率低于经典单核细胞，并上调不同的细胞表面标志。在稳定状态下，这些非经典单核细胞将花费更长的时间沿着内皮非定向爬行以观察血管系统，尽管更常见于较小的血管而不是较大的血管。我们发现，在动脉粥样硬化形成过程中，通过给小鼠喂食高脂肪和高胆固醇的西方饮食，非经典单核细胞的巡逻活动显著增加。我们实验室以前的工作表明，这些单核细胞具有动脉粥样硬化保护作用，因为它们的缺失会导致斑块大小和炎性单核细胞数量的增加。这些非经典单核细胞在动脉粥样硬化中的作用以及巡逻的确切机制尚不清楚，但通过研究非经典单核细胞是如何被这种疾病激活的，我们可能能够阐明治疗血管炎症和斑块形成的新靶点。