Center for Research on Reproduction and Women's Health, University of Pennsylvania, Philadelphia, PA, United States.
Department of Surgery, Perelman School of Medicine, University of Pennsylvania, PA, United States.
Front Immunol. 2021 Oct 4;12:741518. doi: 10.3389/fimmu.2021.741518. eCollection 2021.
Intrauterine inflammation impacts prenatal neurodevelopment and is linked to adverse neurobehavioral outcomes ranging from cerebral palsy to autism spectrum disorder. However, the mechanism by which a prenatal exposure to intrauterine inflammation contributes to life-long neurobehavioral consequences is unknown. To address this gap in knowledge, this study investigates how inflammation transverses across multiple anatomic compartments from the maternal reproductive tract to the fetal brain and what specific cell types in the fetal brain may cause long-term neuronal injury. Utilizing a well-established mouse model, we found that mid-gestation intrauterine inflammation resulted in a lasting neutrophil influx to the decidua in the absence of maternal systemic inflammation. Fetal immunologic changes were observed at 72-hours post-intrauterine inflammation, including elevated neutrophils and macrophages in the fetal liver, and increased granulocytes and activated microglia in the fetal brain. Through unbiased clustering, a population of Gr-1+ γ/δ T cells was identified as the earliest immune cell shift in the fetal brain of fetuses exposed to intrauterine inflammation and determined to be producing high levels of IFNγ when compared to γ/δ T cells in other compartments. In a case-control study of term infants, IFNγ was found to be elevated in the cord blood of term infants exposed to intrauterine inflammation compared to those without this exposure. Collectively, these data identify a novel cellular immune mechanism for fetal brain injury in the setting of intrauterine inflammation.
子宫内炎症会影响产前神经发育，并与从脑瘫到自闭症谱系障碍等各种不良神经行为后果相关。然而，产前暴露于子宫内炎症如何导致终身神经行为后果的机制尚不清楚。为了解决这一知识空白，本研究探讨了炎症如何从母体生殖道跨越多个解剖隔室传播到胎儿大脑，以及胎儿大脑中的哪些特定细胞类型可能导致长期神经元损伤。利用一种成熟的小鼠模型，我们发现子宫内炎症在没有母体全身炎症的情况下，导致妊娠中期胎儿蜕膜中持续存在中性粒细胞浸润。在宫内炎症后 72 小时观察到胎儿免疫变化，包括胎儿肝脏中中性粒细胞和巨噬细胞增多，以及胎儿大脑中粒细胞和活化的小胶质细胞增多。通过无偏聚类，鉴定出一群 Gr-1+γ/δ T 细胞，这是胎儿大脑中最早的免疫细胞变化，与其他隔室中的 γ/δ T 细胞相比，这些细胞产生高水平的 IFNγ。在一项足月婴儿的病例对照研究中，与没有这种暴露的婴儿相比，暴露于子宫内炎症的足月婴儿的脐血中发现 IFNγ 升高。总的来说，这些数据确定了子宫内炎症情况下胎儿脑损伤的新的细胞免疫机制。
