1 Department of Obstetrics and Gynecology, Maternal and Child Health Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Reprod Sci. 2019 Aug;26(8):1082-1093. doi: 10.1177/1933719118805859. Epub 2018 Nov 21.
Exposure to intrauterine inflammation during pregnancy is linked to brain injury and neurobehavioral disorders in affected children. Innate immunity, specifically Toll-like receptor (TLR) signaling pathways are present throughout the reproductive tract as well as in the placenta, fetal membranes, and fetus. The TLR pathways are mechanistically involved in host responses to foreign pathogens and may lead to brain injury associated with prenatal inflammation.
We aimed to determine whether the activation of the TLR4 signaling pathway, in the mother and fetus, is critical to fetal brain injury in the setting of intrauterine inflammation.
A mini-laparotomy was performed on time pregnant C57B6 mice and 2 knockout mouse strains lacking the function of the and genes on embryonic day 15. Intrauterine injections of lipopolysaccharide or saline were administered as described previously. Dams were killed 6 hours postsurgery, and placental, amniotic fluid, and fetal brain tissue were collected. To assess brain injury, quantitative polymerase chain reaction (qPCR) analysis was performed on multiple components of the NOTCH signaling pathway, including genes. Interleukin (IL) IL6, IL1β, and CCL5 expression was assessed using qPCR and enzyme-linked immunosorbent assay.
Using an established mouse model of intrauterine inflammation, we demonstrate that the abrogation of TLR4 signaling eliminates the cytokine response in mother and fetus and prevents brain injury associated with increased expression of transcriptional effectors of the NOTCH signaling pathway, and .
These data show that the activation of the TLR4 signaling pathway is necessary for the development of fetal brain injury in response to intrauterine inflammation.
孕期宫内炎症暴露与受影响儿童的脑损伤和神经行为障碍有关。先天免疫，特别是 Toll 样受体（TLR）信号通路存在于整个生殖道以及胎盘、胎膜和胎儿中。TLR 通路在宿主对外来病原体的反应中具有机械作用，并且可能导致与产前炎症相关的脑损伤。
我们旨在确定 TLR4 信号通路在母体和胎儿中的激活是否对宫内炎症情况下胎儿脑损伤至关重要。
对怀孕时间为 15 天的 C57B6 小鼠和 2 种缺乏 和 基因功能的基因敲除小鼠进行微创剖腹术。如前所述，宫内注射脂多糖或生理盐水。手术后 6 小时处死母鼠，收集胎盘、羊水和胎脑组织。为了评估脑损伤，对 NOTCH 信号通路的多个成分（包括 基因）进行了定量聚合酶链反应（qPCR）分析。使用 qPCR 和酶联免疫吸附试验评估白细胞介素（IL）IL6、IL1β 和 CCL5 的表达。
使用已建立的宫内炎症小鼠模型，我们证明 TLR4 信号通路的阻断消除了母体和胎儿中的细胞因子反应，并防止了与 NOTCH 信号通路转录效应物 和 表达增加相关的脑损伤。
这些数据表明，TLR4 信号通路的激活是胎儿脑损伤对宫内炎症反应的必要条件。
