Preclinical imaging of immune responses to chronic stress

摘要 心理社会压力在几个阶段导致心血管疾病，包括促进 冠状动脉疾病进展和急性触发心脏事件1，2。在这个项目中，我们的目标是研究 急性和慢性应激暴露及其对免疫系统和 动脉硬化。我们将通过开发和应用非专利技术来解决这些重要问题 侵入性成像方法。 应激激活大脑中的各种信号回路，包括下丘脑-垂体-肾上腺(HPA) 轴和交感神经系统(SNS)，从而影响白细胞的分布和功能 以及动脉粥样硬化性斑块炎症。具体地说，急性应激控制期间HPA轴的激活 淋巴细胞和单核细胞归巢到骨髓，而中性粒细胞则迅速从骨骼中动员出来 运动皮质信号所致的骨髓3。同时，SNS的激活导致儿茶酚胺的产生， 它们基于代谢和表观遗传学在单核细胞中诱导持久的促炎表型 应激引起的SNS激活也与动脉粥样硬化斑块的增强直接相关 在慢性应激暴露期间，直接交感神经信号增强血管内皮细胞的增殖 骨髓中的造血干细胞和祖细胞(HSPC)(造血)，导致更高 循环中的促炎中性粒细胞和单核细胞数6，8。这些细胞随后渗出 进入动脉壁并增强斑块炎症。 我们假设，应激暴露通过以下途径对免疫系统产生长期影响 训练免疫的诱导和髓系细胞动力学的变化。在这个高度创新的项目中，我们将 使用新开发和建立的PET成像方法来探测应激对免疫的影响 系统和动脉粥样硬化斑块纵向、体内和全身水平的炎症。在目标1中，我们 将重点放在应激暴露过程中造血器官的新陈代谢和表观遗传重排 在压力戒断之后。AIM 2围绕应激诱导的髓系细胞动力学(细胞)改变而进化 增殖、迁移、外流和髓系细胞负担)，通过复杂的成像方法进行探测。 完成这些目标将有助于破译压力对免疫力的直接和长期影响 分子生物学和免疫学与最先进的翻译技术的独特结合 心血管成像研究。

SUMMARY Psychosocial stress contributes to cardiovascular disease at several stages, including promoting coronary artery disease progression and acutely triggering cardiac events1,2. In this project, we aim to investigate both acute and chronic stress exposure and their immediate and long-term effects on the immune system and atherosclerosis. We will approach these important questions through the development and application of non- invasive imaging methods. Stress activates diverse signaling circuits in the brain, including the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS), which subsequently affect leukocyte distribution and function as well as atherosclerotic plaque inflammation. Specifically, HPA axis activation during acute stress controls lymphocyte and monocyte homing to the bone marrow, while neutrophils are rapidly mobilized from the bone marrow due to motor cortex signaling3. In parallel, SNS activation leads to the production of catecholamines, which induce a long-lasting pro-inflammatory phenotype in monocytes based on metabolic and epigenetic rewiring4,5. SNS activation due to stress has also been directly linked to enhanced atherosclerotic plaque inflammation6,7. During chronic stress exposure, direct sympathetic signaling enhances the proliferation of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (hematopoiesis), leading to higher numbers of circulating pro-inflammatory neutrophils and monocytes6,8. These cells subsequently extravasate into the arterial wall and enhance plaque inflammation. We hypothesize that stress exposure induces long-term effects on the immune system through the induction of trained immunity and changes in myeloid cell dynamics. In this highly innovative project, we will employ newly developed and established PET imaging methods to probe stress’s effects on the immune system and atherosclerotic plaque inflammation longitudinally, in vivo, and at a whole-body level. In Aim 1, we will focus on metabolic and epigenetic rewiring in hematopoietic organs over the course of stress exposure and after stress withdrawal. Aim 2 evolves around stress-induced alterations in myeloid cell dynamics (cell proliferation, migration, egress, and myeloid cell burden), probed by sophisticated imaging methods. Completing these Aims will help decipher stress’s immediate and long-term impact on the immune system though unique integration of molecular biology and immunology with state-of-the-art translational cardiovascular imaging research.