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.

项目摘要/摘要：慢性压力会促进全身炎症反应，从而导致心血管疾病和代谢疾病（CVD），甚至急剧增加的压力都会加剧疾病的严重程度。在人类中，高脂肪/高胆固醇饮食（HFD）的消耗是导致慢性应激反应的常见辅助因素。了解控制应激反应的机制及其与 CVD 疾病的关联，这些机制是几乎无处不在，并且是死亡的主要原因，将有助于开发有影响力的转化技术对抗这种尚未充分研究的疾病的方法。 AG 是类固醇激素的主要来源，皮质酮和醛固酮是在皮质中产生的。皮质酮升高会改变血糖体内平衡、免疫和组织重塑。我们之前使用低温应力模型的工作表明冷应激会促进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压力做出反应通过冷暴露或 HFD 喂养来缓解反应。有趣的是，我们观察到体内脂质的积累在动脉粥样硬化模型中，AG 常驻巨噬细胞与产生激素的内分泌细胞相邻，高血压，或急性感冒挑战。组织驻留巨噬细胞通常是组织修复细胞和脂质积累与巨噬细胞的抗炎表型相关。 AG巨噬细胞尚未文献中有详细描述，但它们响应激素信号的功能尚不清楚。通过我们的对 WT 小鼠（没有明显应激源的饮食喂养）的初步研究，我们确定了两个主要群体 AG 中存在巨噬细胞。这些人群在代表性方面表现出性别二态性比较成年雄性与雌性小鼠时的巨噬细胞亚群。此外，通过单细胞RNA- 通过对男性和女性 AG 免疫群体之间的 seq 分析，我们确定了与 AG 常驻巨噬细胞并发现脂质传感器 Trem2 的组成型表达，该信号被发现慢性攻击后 AG 巨噬细胞增加，支持对脂质激素的反应。 Trem2 的缺失与 AG 中的脂质积累和循环皮质酮水平升高有关在没有挑战的情况下。总之，这些观察结果得出了 AG 居民的总体假设巨噬细胞的维持是由性激素的产生控制的，AG巨噬细胞感知应激反应期间的类固醇激素可抑制炎症并促进组织健康。我们的在研究组织巨噬细胞的发育和功能以及利用新的动物模型使我们的团队成为测试这些新颖概念的理想选择。如果属实，这项研究的意义将确定通过调节 AG 相关蛋白来调节全身炎症反应的新方法巨噬细胞，这可能会补充目前用于高危心血管疾病患者的脂质控制方法。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Trem2 promotes foamy macrophage lipid uptake and survival in atherosclerosis.

Trem2 促进动脉粥样硬化中泡沫巨噬细胞的脂质摄取和存活。

DOI：
发表时间：
2023-11
期刊：
影响因子：
0
作者：
Patterson, Michael T;Firulyova, Maria M;Xu, Yingzheng;Hillman, Hannah;Bishop, Courtney;Zhu, Alisha;Hickok, Grant H;Schrank, Patricia R;Ronayne, Christine E;Caillot, Zakariya;Fredrickson, Gavin;Kennedy, Ainsley E;Acharya, Nisha;Neels, Jaap G
通讯作者：
Neels, Jaap G

Macrophage Fate Mapping.

巨噬细胞命运图谱。