Psychosocial stress' effects on macrophage dynamics in atherosclerosis

摘要 动脉粥样硬化是心肌梗死和中风的根本原因，是一种由脂质驱动的 以脂蛋白和白细胞聚集为特征的慢性炎症性疾病 血管壁。在白细胞中，单核细胞来源的内膜巨噬细胞可以说是最多的 对发展、进展、恶化和退化起决定性作用的因素 动脉硬化。作为炎症、蛋白质分解、氧化应激、脂质清除的关键效应者， 巨噬细胞长期以来一直是治疗红斑狼疮的靶点。 动脉硬化。然而，血管壁中的巨噬细胞含量是高度动态的，依赖于 由不同的生物途径控制的多个系统和局部过程。 最近，我们发现，心理社会压力会加剧心血管疾病， 通过干扰巨噬细胞供应链加剧动脉粥样硬化；动物受到 间歇性心理社会应激导致炎性皮损 巨噬细胞多于对照组。在这个项目中，我们将询问压力如何影响与以下相关的机制 单核细胞的流入(骨髓再生，单核细胞和干细胞的动员， 髓外骨髓生成，单核细胞流入病变)，病变中巨噬细胞增多 (巨噬细胞分化和局部增殖)和巨噬细胞外流(巨噬细胞死亡 通过细胞凋亡、坏死或继发性坏死，以及巨噬细胞迁移)。总而言之， 我们称之为巨噬细胞动力学。我们将调查压力对 巨噬细胞动力学在动脉粥样硬化进展和消退中的作用 交感神经系统和神经引导线索。我们将确定决定 控制与巨噬细胞动力学相关的过程的节点，最终目的是靶向 从治疗上来说。

SUMMARY Atherosclerosis, the underlying cause of myocardial infarction and stroke, is a lipid-driven chronic inflammatory disease characterized by lipoprotein and leukocyte accumulation in the vessel wall. Among leukocytes, monocyte-derived intimal macrophages are arguably the most decisive contributors to the development, progression, exacerbation, and regression of atherosclerosis. As key effectors of inflammation, proteolysis, oxidative stress, lipid clearance, and efferocytosis, macrophages have long been therapeutic targets for the treatment of atherosclerosis. However, macrophage content in the vessel wall is highly dynamic, relying on multiple systemic and local processes that are governed by distinct biological pathways. Recently, we showed that psychosocial stress, which potentiates cardiovascular disease (CVD), aggravates atherosclerosis by disturbing the macrophage supply chain; animals subjected to intermittent psychosocial stress developed inflamed lesions containing more numerous macrophages than controls. In this project, we will ask how stress affects mechanisms related to influx of monocytes (medullary myelopoiesis, mobilization of monocytes and stem cells, extramedullary myelopoiesis, and monocyte influx to lesions), macrophage accrual in lesions (macrophage differentiation and local proliferation), and macrophage efflux (macrophage death through apoptosis, necrosis, or secondary necrosis, and macrophage emigration). Collectively, we refer to these as macrophage dynamics. We will investigate the impact of stress on macrophage dynamics in the progression and regression of atherosclerosis, with specific focus on the sympathetic nervous system and neuronal guidance cues. We will identify the decision nodes that control processes related to macrophage dynamics with the ultimate aim of targeting them therapeutically.