Prenatal stress challenge in mice: the role of vertically transmitted maternal glucocorticoids and immune cells in modulating offspring‘s immunity

小鼠产前应激挑战：垂直传播的母体糖皮质激素和免疫细胞在调节后代免疫力中的作用

• 批准号: 269321214
• 负责人: Professorin Dr. Petra Clara Arck
• 金额: --
• 依托单位: Klinik für Geburtshilfe und Pränatalmedizin
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/269321214?language=en
• 关键词: Prenatal; stress; challenge; mice; role

Epidemiological studies highlight that stress exposure during pregnancy increases the prevalence of infectious and chronic immune diseases later in life of the offspring. During pregnancy, tailored maternal immune and endocrine adaptations tightly control foetal development. These adaptations are highly susceptible to environmental cues, such as stress challenge. Insights into distinct pathways causally linking maternal mediators altered in response to stress challenge to an impaired foetal immune development are largely unknown. In mice, we could mimic the increased vulnerability of the adult offspring for chronic immune diseases (asthma) in response to prenatal stress. This effect was sex-specific, as female offspring were primarily affected. During the first funding period of the KFO296, we demonstrated that prenatal stress challenge tilts the maternal immune responses towards inflammation and activates the maternal hypothalamic-pituitary-adrenal axis, resulting in excess glucocorticoids not only in pregnant mice, but also their foetuses. Further, we established the detection of maternal cells in immune organs of the foetus and confirmed that they are retained until adulthood. As these cells occur at low frequencies, they are referred to as maternal microchimeric cells. Indeed, we observed a reduced frequency of maternal microchimeric cells in foetal bone marrow in response to stress. In depth analysis of the foetal bone marrow revealed an altered immune development upon stress, mirrored by decreased common myeloid progenitor cells and monocytes. Interestingly, in vitro experiments underscored that maternal microchimeric cells favour haematopoiesis towards the generation of monocytes. Further, when analysing bone marrow-derived haematopoietic stem cells from prenatally stressed adult offspring, a differential methylation of promoter regions was detectable, which included genes regulating myeloid cell differentiation. Noteworthy, lung development was also altered in prenatally stressed offspring. Based on these intriguing findings, we now seek to test the hypothesis that prenatal stress – via increased levels of maternal glucocorticoids and altered frequency and phenotype of maternal microchimeric cells - alters the lineage-specific epigenetic differentiation processes of haematopoietic stem cells, subsequently affecting offspring’s’ immunity. These alterations confer an increased susceptibility for infections, but also chronic immune diseases such as asthma or allergies.

流行病学研究突出表明，怀孕期间的压力暴露会增加后代以后生活中传染病和慢性免疫疾病的患病率。在怀孕期间，量身定制的母体免疫和内分泌适应严格控制胎儿发育。这些适应非常容易受到环境因素的影响，例如压力挑战。对于将因应对压力挑战而改变的母体介质与胎儿免疫发育受损之间存在因果关系的不同途径的见解在很大程度上尚不清楚。在小鼠中，我们可以模拟成年后代对慢性免疫疾病（哮喘）的脆弱性增加，以应对产前压力。这种影响是性别特异性的，因为雌性后代主要受到影响。在KFO 296的第一个资助期内，我们证明产前应激挑战会使母体免疫反应向炎症倾斜，并激活母体下丘脑-垂体-肾上腺轴，不仅导致怀孕小鼠及其胎儿产生过量的糖皮质激素。此外，我们建立了胎儿免疫器官中母体细胞的检测，并证实它们保留到成年。由于这些细胞以低频率出现，它们被称为母体微嵌合细胞。事实上，我们观察到胎儿骨髓中母体微嵌合体细胞在应激反应中的频率降低。对胎儿骨髓的深入分析揭示了应激后免疫发育的改变，这反映在共同骨髓祖细胞和单核细胞的减少上。有趣的是，体外实验强调，母体微嵌合细胞有利于造血对单核细胞的产生。此外，当分析来自产前应激的成年后代的骨髓来源的造血干细胞时，可检测到启动子区域的差异甲基化，其中包括调节髓样细胞分化的基因。值得注意的是，肺发育也改变了产前强调后代。基于这些有趣的发现，我们现在试图验证这样的假设，即产前应激-通过母体糖皮质激素水平的增加和母体微嵌合细胞频率和表型的改变-改变造血干细胞的谱系特异性表观遗传分化过程，随后影响后代的免疫力。这些改变增加了感染的易感性，也增加了慢性免疫疾病，如哮喘或过敏。