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: 10229462
• 负责人: Andrea Goldberg Edlow
• 金额: $ 39.46万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10229462
• 关键词: Ablation; Adaptor Signaling Protein; Adolescent; Adult Children; Affect; Age; Anti-Inflammatory Agents; Antigens; Anxiety; Attention deficit hyperactivity disorder; Behavior; Biological; Body mass index; 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; diet-induced obesity; 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.

项目概要 在美国，三分之一的育龄妇女患有肥胖症。在大型流行病学研究中，孕产妇肥胖。 肥胖与儿童认知缺陷有关，包括智商降低和低（<70）以及阅读能力较低 和数学分数的潜在机制仍不清楚。目前已知的是，母亲肥胖是一种状态。 据报道，胎儿存在慢性低水平免疫激活以及胎盘和脑部炎症 以及肥胖女性的后代，小胶质细胞是大脑的常驻免疫细胞，与该疾病有关。 许多神经发育疾病的发病机制在后代中频率增加 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。 我们已经证明了胎儿大脑转录组的性别特异性。 产妇肥胖的背景，免疫和炎症信号失调是关键影响 我们随后证明了母亲肥胖对男性和女性胚胎大脑的显着影响。 母亲肥胖对胚胎小胶质细胞抗原（Iba-1）密度的性别二态性影响 肥胖后代的海马体和海马体学习缺陷，其中男性后代更多 这些数据支持胚胎生命中大脑免疫激活异常的假设。 是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产生终生的神经发育后果，但直接 幸运的是，评估活体人类胎儿或新生儿的小胶质细胞功能是不可能的。 巨噬细胞（霍夫鲍尔细胞）和小胶质细胞在胎儿卵黄囊中具有共同起源。 巨噬细胞是人一生中永久性的脑小胶质细胞池。 胎盘霍夫鲍尔细胞代表了一种潜在的新型生物哨兵，可能反映小胶质细胞 在这里，我们试图检验以下假设：(1a) 母亲肥胖会引发 Hofbauer。 细胞和胎儿大脑小胶质细胞对免疫挑战过度反应 (1b) 母亲肥胖将导致关键 胎儿小胶质细胞单细胞转录组的改变将在霍夫鲍尔细胞中重现 转录组 (2) 胎儿大脑和胎盘中促炎巨噬细胞信号传导的选择性消融 使用创新的转基因小鼠将挽救与肥胖相关的母亲海马学习缺陷。 拟议的实验将通过确定是否增加促炎症来填补知识空白 胎盘和胎儿大脑中的巨噬细胞信号传导是后代海马学习的潜在机制 证明胎儿胎盘和脑巨噬细胞介导的缺陷之间存在因果关系。 如果 Hofbauer 细胞可以的话，炎症和神经发育疾病具有潜在的治疗应用。 作为一种更容易获得的细胞类型，可以提供有关胎儿大脑小胶质细胞行为的信息， 可能对评估肥胖以外的母亲暴露情况下的后代风险具有更广泛的影响。