Maternal obesity and neonatal innate immunity

发育中的胎儿免疫系统对来自母体的信号非常敏感。 环境孕妇怀孕前（pregravid）肥胖已成为最常见的肥胖之一。 胎儿健康的重要调节者。临床和动物模型研究数据 表明对微生物感染的易感性增加， 炎症性疾病和自身免疫性疾病与母体肥胖。这种二分法是 通过脾细胞对LPS刺激产生抑制的炎症反应来说明， 肠道内的免疫细胞会产生夸张的免疫细胞。同样，妊娠前肥胖导致 静息时脐带血单核细胞炎症基因表达较低，但 分化为巨噬细胞时，炎性基因的表达显著增加。 这些观察结果强烈表明，妊娠前肥胖破坏了发育， 胎儿免疫系统的成熟和差异影响循环单核细胞 和组织驻留巨噬细胞（TRM）。然而，这一现象的分子基础 由于难以获得术语，对母亲肥胖引起的调节障碍仍然知之甚少。 胎儿组织和控制多个母体变量，调节胎儿免疫。因此，在本发明中， 在这个应用中，我们将利用恒河猴模型来询问多个胎儿， 在同一个主题中，我们可以找到一些不同的内容，以弥补这一知识差距。免疫个体发生 通过3种不同的波，从卵黄囊开始，过渡到胎儿肝脏，最后是骨髓。 TRM主要来源于卵黄囊和胎肝，而循环单核细胞来源于 从骨髓中提取我们最近报道，妊娠前肥胖与低级别 因怀孕而进一步恶化的炎症。因此，我们假设， 分级母体炎症导致TRM的“训练”，而升高的母体炎症 妊娠晚期的环境导致骨髓来源的单核细胞的“耐受性”。因此，我们认为， 本申请将检验中心假设，即妊娠前肥胖会导致 TRM和循环单核细胞的重新布线，其中TRM准备产生一种新的免疫应答。 炎症反应增强，而循环单核细胞显示发育不良， 反应这种应用的新奇在于系统生物学方法整合了 在多重免疫中获得的具有基因组和功能读数的母体临床元数据 在同一个动物身上。完成拟议的实验将揭示 导致胎儿巨噬细胞和单核细胞功能改变的分子机制， 为早期干预的潜在发展提供信息。

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.