Maternal obesity and neonatal innate immunity

发育中的胎儿免疫系统对母体发出的信号非常敏感 环境。孕妇孕前(孕前)肥胖已成为最严重的 胎儿健康的相应调节者。来自临床和动物模型研究的数据 显示出对微生物感染的易感性增加，以及更高的发病率 与母亲肥胖有关的炎症性疾病和自身免疫性疾病。这种二分法是 脾细胞对内毒素刺激产生抑制的炎症反应，而 肠道常驻免疫细胞会产生夸大的免疫细胞。同样，孕前肥胖会导致 静息状态下脐血单核细胞中炎性基因表达降低 分化为巨噬细胞后，炎症基因表达明显增强。 这些观察有力地表明，孕前肥胖破坏了发育和 胎儿免疫系统的成熟及其对循环单核细胞的不同影响 和组织驻留巨噬细胞(TRMS)。然而，这其中的分子基础 由于很难获得足月分娩，母体肥胖引起的调节失调仍然知之甚少。 胎儿组织和控制调节胎儿免疫的多个母体变量。因此， 在本应用程序中，我们将利用恒河猴模型来询问多个胎儿 在同一主题内的隔间，以解决这一知识鸿沟。免疫个体发育发生 经过3个不同的波，从卵黄囊开始，过渡到胎肝，最后是骨髓。 TRMS主要来自卵黄囊和胎肝，而循环单核细胞主要来自于 从骨髓中提取。我们最近报道，孕前肥胖与低度肥胖有关。 因怀孕而进一步加重的炎症。因此，我们假设暴露在低风险中 母体炎症分级导致TRMS的“训练”，同时加剧母体炎症 妊娠晚期的环境导致骨髓来源的单核细胞“耐受”。因此， 这个应用程序将检验孕前肥胖导致差异的中心假设 重新连接TRMS和循环单核细胞，其中TRMS准备产生 当循环单核细胞表现为发育迟缓时，炎症反应增强 回应。这一应用的新奇之处在于系统生物学方法的集成 在多重免疫中获得基因组和功能读数的产妇临床元数据 同一动物体内的隔间。拟议的实验完成后，将揭示 导致胎儿巨噬细胞和单核细胞功能改变的分子机制 告知早期干预措施的潜在发展。

The developing fetal immune system is exquisitely sensitive to signals from the maternal environment. Maternal pre-pregnancy (pregravid) obesity has emerged as one of the most consequential regulators of fetal health. Data from clinical and animal model studies demonstrated increased susceptibility to microbial infection as well as a higher incidence of inflammatory disorders and auto-immune diseases with maternal obesity. This dichotomy is illustrated by splenocytes generating dampened inflammatory responses to LPS stimulation while gut resident immune cells generate exaggerated ones. Similarly, pregravid obesity resulted in lower expression of inflammatory genes in umbilical cord blood monocytes at rest, but following differentiation into macrophages, expression of inflammatory genes was significantly increased. These observations strongly suggest that pregravid obesity disrupts the development and maturation of the fetal immune system and differentially impacts circulating monocytes and tissue resident macrophages (TRMs). However, the molecular underpinnings of this dysregulation by maternal obesity remain poorly understood due to the difficulty of obtaining term fetal tissues and of controlling for multiple maternal variables that modulate fetal immunity. Thus, in this application, we will leverage the rhesus macaque model to interrogate multiple fetal compartments within the same subject to address this knowledge gap. Immune ontogeny occurs via 3 different waves starting with yolk sac, transitioning to fetal liver, and finally the bone marrow. TRMs are derived primarily from yolk sac and fetal liver while circulating monocytes are derived from bone marrow. We recently reported that pregravid obesity is associated with low grade inflammation that is further compounded by pregnancy. Thus, we postulate that exposure to low grade maternal inflammation leads to “training” of TRMs while heightened maternal inflammatory environment in late gestation leads to “tolerance” of bone marrow derived monocytes. Therefore, this application will test the central hypothesis that pregravid obesity results in differential rewiring of TRMs and circulating monocytes wherein TRMs are poised to generate a heightened inflammatory response while circulating monocytes display a stunted response. The novelty of this application lies in the systems biology approach integrating maternal clinical metadata with genomic and functional readouts obtained in multiple immune compartments in the same animal. Completion of the proposed experiments will reveal the molecular mechanisms that result in altered fetal macrophage and monocyte functions thus informing the potential development of early interventions.