Institute for Stem Cell Biology and Regenerative Medicine and Department of Neurosurgery, Stanford University, Stanford, California, USA.
Am J Pathol. 2011 Jun;178(6):2802-10. doi: 10.1016/j.ajpath.2011.02.042.
Maternal infections are implicated in a variety of complications during pregnancy, including pregnancy loss, prematurity, and increased risk of neurodevelopmental disorders in the child. Here, we show in mice that even mild innate immune activation by low-dose lipopolysaccharide in early pregnancy causes hemorrhages in the placenta and increases the risk of pregnancy loss. Surviving fetuses exhibit hypoxia in the brain and impaired fetal neurogenesis. Maternal Toll-like receptor 4 signaling is a critical mediator of this process, and its activation is accompanied by elevated proinflammatory cytokines in the placenta. We evaluated the role of tumor necrosis factor-α (TNF-α) signaling and show that TNF receptor 1 (TNFR1) is necessary for the illness-induced placental pathology, accompanying fetal hypoxia, and neuroproliferative defects in the fetal brain. We also show that placental TNFR1 in the absence of maternal TNFR1 is sufficient for placental pathology to develop and that a clinically relevant TNF-α antagonist prevents placental pathology and fetal loss. Our observations suggest that the placenta is highly sensitive to proinflammatory signaling in early pregnancy and that TNF-α is an effective target for preventing illness-related placental defects and related risks to the fetus and fetal brain development.
母体感染与怀孕期间的多种并发症有关，包括妊娠丢失、早产以及儿童神经发育障碍的风险增加。在这里，我们在小鼠中表明，即使在妊娠早期低剂量脂多糖引起的轻度固有免疫激活也会导致胎盘出血，并增加妊娠丢失的风险。存活的胎儿表现出大脑缺氧和胎儿神经发生受损。母体 Toll 样受体 4 信号是该过程的关键介质，其激活伴随着胎盘内促炎细胞因子的升高。我们评估了肿瘤坏死因子-α（TNF-α）信号的作用，并表明 TNF 受体 1（TNFR1）对于疾病引起的胎盘病理、伴随的胎儿缺氧以及胎儿大脑神经增殖缺陷是必需的。我们还表明，缺乏母体 TNFR1 的胎盘 TNFR1 足以导致胎盘病理发生，并且一种临床相关的 TNF-α 拮抗剂可预防胎盘病理和胎儿丢失。我们的观察表明，胎盘对妊娠早期的促炎信号非常敏感，TNF-α是预防与疾病相关的胎盘缺陷以及对胎儿和胎儿大脑发育相关风险的有效靶点。
