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

项目摘要/摘要： 慢性应激促进全身性炎症反应，从而促进心血管和 代谢性疾病(CVD)，甚至急剧增加的压力都会加剧疾病的严重性。在人类身上， 食用高脂肪/高胆固醇饮食(HFD)是推动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心血管疾病的关系，这些机制包括 几乎无处不在并且是死亡的主要原因，将允许发展有影响力的翻译 与这种未被研究的疾病作斗争的方法。AG是类固醇激素的主要来源， 皮质中产生的皮质酮和醛固酮。皮质酮升高对血糖的影响 动态平衡、免疫力和组织重塑。我们之前使用冷温应力模型所做的工作表明 这种冷应激促使单核细胞从骨髓中排出，加剧了动脉粥样硬化。 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，我们观察到脂肪在 在动脉粥样硬化模型中，银驻留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。组织驻留巨噬细胞是典型的组织修复细胞和脂质 巨噬细胞中的积聚与抗炎表型有关。Ag巨噬细胞还没有 文献中对它们进行了详细的描述，它们对激素信号的反应功能尚不清楚。通过我们的 对WT小鼠(饲喂无明显应激源的饲料)的初步研究，我们确定了两个主要群体 巨噬细胞存在于AG内。这些群体表现出性别的二型性在代表 比较成年雄性小鼠和雌性小鼠时的巨噬细胞亚群。此外，通过单细胞RNA- 在男性和女性AG免疫群体之间的SEQ图谱，我们确定了与 AG驻留巨噬细胞，并发现脂质传感器TREM2的结构性表达，发现 在慢性攻击后，AG巨噬细胞的数量增加，支持了对脂类激素的反应。 TREM2的丢失与AG中的脂质堆积和循环皮质酮水平升高有关 在没有挑战的情况下。总而言之，这些观察结果导致了总体假说AG居民 巨噬细胞的维持受性激素的产生控制，AG巨噬细胞感觉 应激反应中的类固醇激素可抑制炎症，促进组织健康。我们的 在研究组织巨噬细胞的发育和功能方面有丰富的经验，以及新的 动物模型使我们小组成为测试这些新概念的理想选择。如果是真的，这项研究的影响将确定 通过调节AG相关蛋白调节全身炎症反应的新途径 巨噬细胞，这可能是对目前用于高危CVD患者的血脂控制方法的补充。

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.