Stress-induced trained immunity in cardiovascular disease

项目总结 在过去的十年里，新出现的证据表明，先天性免疫系统保持了很长时间- 感染或接种疫苗后的表观遗传和代谢变化。这种事实上的先天免疫记忆 已被称为“训练免疫”，其特点是髓系细胞的高反应性 随后的刺激措施。最近的研究表明，无菌的动脉粥样硬化/炎症诱因，如 氧化的低密度脂蛋白或儿茶酚胺，类似地通过表观遗传和 髓系隔室的代谢重新编程。训练有素的免疫在中国的长期坚持 VIVO是由于骨髓中的造血干细胞和祖细胞(HSPC)的重新编程所致。 我们最近报道，从有心血管疾病危险因素的患者中分离出的单核细胞，如 家族性高胆固醇血症或嗜铬细胞瘤，表现为“训练有素”的表型。重要的是，在患者中 在确诊的冠状动脉疾病中，我们发现HSPC被重新编程为促炎因子 髓系血统。项目2将集中在应激诱导的训练性免疫的机制方面 心血管疾病患者和小鼠模型。我们的中心假设是慢性压力会导致 通过HSPC重新编程训练免疫，这会加剧动脉粥样硬化的发展和 会恶化心血管事件的结局。 在目标1中，我们将使用深入的表型和成像来研究心血管疾病的高危患者。 事件，以获得应激诱导的髓系细胞重新编程的综合视图 车厢。在目标2中，我们将研究暴露于慢性轻度心理社会应激或KEY的小鼠 荷尔蒙信号促进压力的外周效应，然后休息4周。后 休息期，应激队列和非应激对照组将接受冠状动脉结扎或诱导 动脉粥样硬化，以检验先前应激或暴露于应激激素会激活这一假设 训练免疫力，从而增加骨髓生成，从而加重心血管疾病。 我们独一无二的能力，可以在Radbouumc、人类模型和小鼠上分析患者的HSPC 模拟它们的模型将产生对心血管疾病和疾病之间关系的关键见解 心理社会压力。

PROJECT SUMMARY In the last decade, emerging evidence has unveiled that the innate immune system retains long- term epigenetic and metabolic changes after infection or vaccination. This de facto innate immune memory has been termed ‘trained immunity’ and is characterized by myeloid cells’ hyper-responsiveness following a subsequent stimulus. Recent work has shown that sterile atherogenic/inflammatory triggers, such as oxidized LDL or catecholamines, similarly induce a trained immunity phenotype through epigenetic and metabolic reprogramming of the myeloid compartment. The long-term persistence of trained immunity in vivo is due to the reprogramming of hematopoietic stem and progenitor cells (HSPC) in the bone marrow. We have recently reported that monocytes isolated from patients with risk factors for CVD, such as familial hypercholesterolemia or pheochromocytoma, display a ‘trained’ phenotype. Importantly, in patients with established coronary artery disease, we found HSPCs reprogrammed towards a pro-inflammatory myeloid lineage. Project 2 will focus on stress-induced trained immunity’s mechanistic aspects in cardiovascular disease patients and mouse models. Our central hypothesis is that chronic stress induces trained immunity via HSPC reprogramming, which exacerbates the development of atherosclerosis and worsens the outcome of cardiovascular events. In Aim 1, we will use deep phenotyping and imaging to study patients at high risk for cardiovascular events in order to obtain an integrated view of stress-induced reprogramming of the myeloid cell compartment. In Aim 2, we will study mice that were exposed to chronic mild psychosocial stress or to key hormonal signals that promote peripheral effects on stress, followed by a rest period of 4 weeks. After the rest period, stressed cohorts and non-stressed controls will undergo coronary artery ligation or induction of atherosclerosis to test the hypothesis that preceding stress or exposure to stress hormones activates trained immunity, thus increasing myelopoiesis and consequently worsening cardiovascular disease. Our unique ability to profile patients’ HSPCs at Radboudumc, the human models, and the mouse models that mimic them will yield critical insights into the relationship between cardiovascular disease and psychosocial stress.