In vivo investigation of non-classical monocyte patrolling mechanism

 描述（由申请人提供）：血液单核细胞主要作为两个亚群在外周循环：经典和非经典或巡逻单核细胞。已经表明，经典单核细胞通过粘附于脉管系统并主要使用选择素和整合素迁移至血管壁的内层，最终成为泡沫细胞，导致血管层内的慢性炎症状态，从而在早期促成动脉粥样硬化的过程。血管的内皮层也被激活，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。已显示非经典单核细胞迁移到斑块部位，尽管它们在斑块内的频率低于经典单核细胞，并且上调不同的细胞表面标志物。在稳态期间，这些非经典单核细胞将花费长时间沿内皮无方向地沿着爬行以调查脉管系统，尽管在较小血管中比在较大血管中更常见。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，因为它们的缺乏会导致斑块大小和炎症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功能以及巡逻的确切机制尚不清楚，但通过研究这种疾病如何激活非经典单核细胞，我们可能能够阐明治疗血管炎症和斑块形成的新靶点。

 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.