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Sex and stress hormones control adrenal gland macrophage development and function"

性激素和应激激素控制肾上腺巨噬细胞的发育和功能"

基本信息

批准号：
10629376
负责人：
Jesse Warren Williams
金额：
$ 43.43万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10629376
关键词：
Acute Adipose tissue Adrenal Cortex Adrenal Glands Adult Aldosterone Animal Model Anti-Inflammatory Agents Arterial Fatty Streak Atherosclerosis Automobile Driving Blood Vessels Bone Marrow Cardiovascular Diseases Castration Cells Cholesterol Chronic Chronic stress Complement Consumption Corticosterone Cytoplasm Development Diet Disease Endocrine Epinephrine Fatty acid glycerol esters Female Gene Expression Genes Genetic Gonadal Steroid Hormones Growth Health Heterogeneity Homeostasis Hormones Human Hypertension Immune Immune response Immune system Immunity In Vitro Inflammation Inflammatory Response Knock-out Knockout Mice Knowledge Lipids Literature Macrophage Maintenance Maps Metabolic Diseases Modeling Morbidity - disease rate Mus Organ Ovariectomy Patients Phenotype Plasma Play Population Production Proliferating Role Severity of illness Source Steroid Receptors Steroids Stress System TREM2 gene Testing Tissues Work biological adaptation to stress blood glucose regulation cardiovascular disorder risk cofactor cold stress cold temperature combat conditional knockout constitutive expression cytokine experience feeding fighting high risk hormonal signals hormone therapy male monocyte mortality mouse model new therapeutic target novel novel strategies programs recruit response sensor sex sexual dimorphism single-cell RNA sequencing steroid hormone stressor systemic inflammatory response therapeutic development tissue repair transcriptomics translational approach uptake virtual

项目摘要

Project Summary/Abstract: Chronic stress promotes a systemic inflammatory response that contributes to cardiovascular and metabolic disease (CVD), and even acutely augmented stress can exacerbate disease severity. In humans, consumption of high fat/high cholesterol diet (HFD) is a common co-factor driving chronic stress responses. Understanding mechanisms controlling the stress-response and its association with CVD diseases, which are nearly ubiquitous and a leading cause of mortality, will allow for development of impactful translational approaches to fight against this understudied disease. The AG is the primary source for steroid hormones, corticosterone and aldosterone that are produced in the cortex. Elevated corticosterone modifies glucose homeostasis, immunity, and tissue remodeling. Our prior work using a cold-temperature stress model showed that cold-stress drives the promotion of monocyte egress from bone marrow and exacerbated atherosclerosis. Therefore, we sought to determine whether the local immune cells in the AG were also responding to stress responses, either through cold-exposure or HFD feeding. Interestingly, we observed accumulation of lipid within AG resident macrophages sitting adjacent to hormone-producing endocrine cells in models of atherosclerosis, hypertension, or acute cold challenge. Tissue resident macrophages are typically tissue repair cells and lipid accumulation is associated with anti-inflammatory phenotypes in macrophages. AG macrophages have not been thoroughly described in literature, and their function in response to hormone signals is unknown. Through our preliminary studies of WT mice (chow-diet fed with no overt stressors), we identified two primary populations of macrophages present in the AG. These populations showed a sexual dimorphism in the representation of macrophage subsets when comparing adult male versus female mice. Furthermore, through single cell RNA- seq profiling between male and female AG immune populations, we identified gene programs associated with AG resident macrophages and found constitutive expression of the lipid-sensor Trem2, which was found to increased on AG macrophages following chronic challenge, supporting a role in responding to lipid-hormones. Loss of Trem2 was associated with lipid accumulation in the AG and elevated circulating corticosterone levels in the absence of challenge. Together, these observations led to the overarching hypothesis AG resident macrophage maintenance is controlled by sex hormone production, and that AG macrophages sense steroid hormones during stress responses to dampen inflammation and promote tissue health. Our extensive experience in studying tissue macrophage development and function, along with the utilization of new animal models make our group ideal to test these novel concepts. If true, the implications of this study will identify new approaches to regulate systemic inflammation responses through the modulation of AG associated macrophages, which might complement current lipid-control approaches used for high-risk CVD patients.

项目概要/摘要：慢性应激促进全身炎症反应，导致心血管疾病，代谢性疾病（CVD），甚至急性加重的压力都可能加剧疾病的严重程度。在人类中，高脂肪/高胆固醇饮食（HFD）的消耗是驱动慢性应激反应的常见辅因子。了解控制应激反应的机制及其与心血管疾病的关系，几乎无处不在，是死亡的主要原因，将允许发展有影响力的翻译来对抗这种未被充分研究的疾病。AG是类固醇激素的主要来源，皮质酮和醛固酮。皮质酮升高改变血糖体内平衡免疫和组织重塑我们先前的工作使用冷温应力模型表明，冷应激促使单核细胞从骨髓中排出并加剧动脉粥样硬化。因此，我们试图确定AG中的局部免疫细胞是否也对应激做出反应反应，无论是通过冷暴露或HFD喂养。有趣的是，我们观察到脂质在在动脉粥样硬化模型中，AG驻留巨噬细胞位于产生分泌物的内分泌细胞附近，高血压或急性寒冷挑战。组织驻留巨噬细胞通常是组织修复细胞和脂质蓄积与巨噬细胞中的抗炎表型有关。AG巨噬细胞尚未被文献中已详细描述，但它们对激素信号反应的功能尚不清楚。通过我们对WT小鼠（无明显应激源的普通饲料喂养）的初步研究，我们确定了两个主要群体，巨噬细胞存在于AG中。这些种群表现出两性异形的代表性，当比较成年雄性与雌性小鼠时，此外，通过单细胞RNA- 在男性和女性AG免疫群体之间的seq分析中，我们鉴定了与以下相关的基因程序： AG驻留巨噬细胞，并发现脂质传感器Trem 2的组成型表达，在慢性攻击后AG巨噬细胞上增加，支持在响应脂质激素中的作用。 Trem 2的缺失与AG中的脂质蓄积和循环皮质酮水平升高相关在没有挑战的情况下。总之，这些观察结果导致了总体假设AG居民巨噬细胞的维持是由性激素的产生控制的，AG巨噬细胞感觉到类固醇激素在压力反应过程中抑制炎症和促进组织健康。我们在研究组织巨噬细胞发育和功能方面的丰富经验，沿着新的动物模型使我们的团队成为测试这些新概念的理想选择。如果是真的，这项研究的意义将确定通过调节AG相关性调节全身炎症反应的新方法巨噬细胞，这可能补充目前用于高风险CVD患者的血脂控制方法。