Fetal Brain-Placental Immune Activation in Maternal Obesity

母亲肥胖中胎儿脑胎盘免疫激活

• 批准号: 10002284
• 负责人: Andrea Goldberg Edlow
• 金额: $ 42.53万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10002284
• 关键词: Ablation; Adaptor Signaling Protein; Adolescent; Adult Children; Affect; Age; Anti-Inflammatory Agents; Antigens; Anxiety; Attention deficit hyperactivity disorder; Behavior; Biological; Brain; Cells; Child; Chronic; Cognitive deficits; Data; Development; Embryo; Encephalitis; Enzyme-Linked Immunosorbent Assay; Evaluation; Female; Fetus; Flow Cytometry; Frequencies; Hippocampus (Brain); Human; Immune; Immune signaling; Individual; Inflammation; Inflammatory; Intervention; Knowledge; Lead; Learning; Learning Disabilities; Life; Link; Lipopolysaccharides; Longevity; Maternal Exposure; Mathematics; Mediating; Mental Depression; Microglia; Morbidity - disease rate; Mus; Myelogenous; Neurocognitive Deficit; Obese Mice; Obesity; Pathogenesis; Placenta; Play; Population; Pre-Clinical Model; Pregnancy; Reading; Reporting; Risk; Role; Saline; Secondary to; Sentinel; Sex Differences; Signal Transduction; Testing; Therapeutic; Thinness; Tissues; Toll-like receptors; Transgenic Mice; United States; Woman; Yolk Sac; autism spectrum disorder; brain cell; cell type; cytokine; density; epidemiology study; experimental study; fetal; immune activation; immune function; immunoreactivity; in utero; innovation; macrophage; male; maternal obesity; mother nutrition; mouse model; neonate; neurodevelopment; novel; obese mothers; offspring; programs; reproductive; response; sex; sexual dimorphism; single-cell RNA sequencing; transcriptome

PROJECT SUMMARY In the United States, one in three women of reproductive age is obese. In large epidemiologic studies, maternal obesity is associated with cognitive deficits in children, including reduced and low IQ (<70), and lower reading and math scores. Underlying mechanisms remain unclear. What is known is that maternal obesity is a state of chronic low-level immune activation, and both placental and brain inflammation have been reported in fetuses and offspring of obese women. Microglia, the resident immune cells of the brain, have been implicated in the pathogenesis of many of the neurodevelopmental morbidities noted with increased frequency in offspring of obese women. Despite this, there is a gap in knowledge about if/how placental inflammation affects fetal brain development in the setting of maternal obesity. We have demonstrated sex-specific fetal brain transcriptomes in the setting of maternal obesity, with dysregulated immune and inflammatory signaling highlighted as key effects of maternal obesity on both the male and female embryonic brain. We subsequently demonstrated a significant and sexually dimorphic effect of maternal obesity on microglial antigen (Iba-1) density in the embryonic hippocampus, and hippocampal learning deficits in obesity-exposed offspring, with male offspring more significantly affected. These data support the hypothesis that aberrant brain immune activation in embryonic life is one mechanism underlying enduring cognitive deficits. Inappropriate fetal microglial priming may therefore have lifelong neurodevelopmental consequences, but direct evaluation of microglial function in a living human fetus or neonate is impossible. Fortunately, placental macrophages (Hofbauer cells) and microglia have a common origin in the fetal yolk sac. Yolk-sac-derived macrophages comprise the permanent pool of brain microglia throughout an individual’s lifetime. Therefore, placental Hofbauer cells represent a potentially novel biologic sentinel that may mirror microglial immunoreactivity. Here, we seek to test the following hypotheses: (1a) maternal obesity will prime both Hofbauer cells and fetal brain microglia to overrespond to an immune challenge (1b) Maternal obesity will induce key alterations in the fetal microglial single cell transcriptome which will be recapitulated in the Hofbauer cell transcriptome (2) Selective ablation of pro-inflammatory macrophage signaling in the fetal brain and placenta using an innovative transgenic mouse will rescue maternal obesity-associated hippocampal learning deficits. The proposed experiments will fill a knowledge gap by ascertaining whether increased pro-inflammatory macrophage signaling in the placenta and fetal brain is a mechanism underlying offspring hippocampal learning deficits in maternal obesity. Demonstrating a causal link between fetal placental and brain macrophage-mediated inflammation and neurodevelopmental morbidity has potential therapeutic applications. If Hofbauer cells can serve as a more accessible cell type that provides information about the behavior of fetal brain microglia, there may be broader implications for assessing offspring risk in the setting of maternal exposures beyond obesity.

项目摘要 在美国，三分之一的育龄妇女肥胖。在大型流行病学研究中， 肥胖与儿童的认知缺陷有关，包括降低和低智商（<70），以及较低的阅读能力 和数学成绩潜在的机制仍不清楚。众所周知，母亲肥胖是一种 在胎儿中已经报道了慢性低水平的免疫激活，以及胎盘和脑炎症 和肥胖女性的后代小胶质细胞是大脑中的常驻免疫细胞， 许多神经发育疾病的发病机制，注意到在后代的频率增加， 肥胖的女人尽管如此，关于胎盘炎症是否/如何影响胎儿大脑的知识仍存在空白 在孕产妇肥胖的背景下发展。我们已经证明了性别特异性胎儿脑转录组， 母亲肥胖的背景，免疫和炎症信号失调是关键影响 对男性和女性胚胎大脑的影响。我们随后展示了一个重要的 母体肥胖对胚胎中小胶质细胞抗原（Iba-1）密度的影响 海马和海马学习缺陷，与男性后代更多 严重影响。这些数据支持胚胎期异常的大脑免疫激活的假设 是导致持久认知缺陷的一种机制 因此，不适当的胎儿小胶质细胞启动可能会导致终身神经发育的后果，但直接影响到胎儿的神经发育。 在活的人类胎儿或新生儿中评价小胶质细胞功能是不可能的。幸运的是胎盘 巨噬细胞（Hofbauer细胞）和小胶质细胞在胎儿卵黄囊中具有共同的起源。卵黄囊源性 巨噬细胞在个体的一生中构成脑小胶质细胞的永久池。因此，我们认为， 胎盘Hofbauer细胞是一种潜在的新型生物哨兵，可能反映小胶质细胞 免疫反应性。在这里，我们试图测试以下假设：（1a）母亲肥胖将启动两个霍夫鲍尔 细胞和胎儿脑小胶质细胞对免疫挑战过度反应（1b）母体肥胖将诱导关键 胎儿小胶质细胞单细胞转录组的改变将在Hofbauer细胞中重现 转录组（2）选择性消除胎脑和胎盘中的促炎性巨噬细胞信号传导 使用创新的转基因小鼠将挽救与母亲肥胖相关的海马学习缺陷。 拟议的实验将填补知识空白，确定增加促炎性是否 胎盘和胎儿脑中的巨噬细胞信号传导是后代海马学习的潜在机制 母亲肥胖的缺陷。证明胎儿胎盘和脑巨噬细胞介导的 炎症和神经发育发病率具有潜在的治疗应用。如果霍夫鲍尔细胞可以 作为一种更容易接近的细胞类型，提供有关胎儿脑小胶质细胞行为的信息， 可能是更广泛的影响，以评估后代的风险，在设置母亲暴露超越肥胖。