The placental interleukin-6 signaling controls fetal brain development and behavior.
The placental interleukin-6 signaling controls fetal brain development and behavior.
复制标题
DOI：
10.1016/j.bbi.2016.11.007
复制
发表时间：
2017-05
期刊：
影响因子：
--
通讯作者：
Patterson PH
中科院分区：
文献类型：
--
作者：
Wu WL;Hsiao EY;Yan Z;Mazmanian SK;Patterson PH
流行病学研究表明，孕期母体免疫激活（MIA）是自闭症的一个危险因素。然而，MIA如何影响后代的大脑发育和行为的机制仍然缺乏描述。为了确定胎盘白细胞介素-6（IL-6）信号传导是否是介导后代MIA所必需的，我们产生了胎盘滋养层中IL-6受体（IL-6 R α）限制性缺失的小鼠（Cyp 19-Cre+; Il 6 rafl/fl），并测试了Cyp 19-Cre+; Il 6 rafl/fl母亲的后代在诱导MIA后的免疫学、病理学和行为异常。我们发现，MIA的结果在胎儿大脑的急性炎症反应。滋养层细胞中缺乏IL-6信号传导可有效阻断MIA诱导的胎盘和胎脑炎症反应。此外，在MIA对照后代中观察到的行为异常和小脑神经病变在Cyp 19-Cre+; Il 6 rafl/fl后代中得到预防。我们的研究结果表明，胎盘中的IL-6活化是将炎症信号传递到胎儿大脑并影响与神经发育疾病相关的行为和神经病理学所必需的。
Epidemiological studies show that maternal immune activation (MIA) during pregnancy is a risk factor for autism. However, mechanisms for how MIA affects brain development and behaviors in offspring remain poorly described. To determine whether placental interleukin-6 (IL-6) signaling is required for mediating MIA on the offspring, we generated mice with restricted deletion of the receptor for IL-6 (IL-6Rα) in placental trophoblasts (Cyp19-Cre+;Il6rafl/fl), and tested offspring of Cyp19-Cre+;Il6rafl/fl mothers for immunological, pathological and behavioral abnormalities following induction of MIA. We reveal that MIA results in acute inflammatory responses in the fetal brain. Lack of IL-6 signaling in trophoblasts effectively blocks MIA-induced inflammatory responses in the placenta and the fetal brain. Furthermore, behavioral abnormalities and cerebellar neuropathologies observed in MIA control offspring are prevented in Cyp19-Cre+;Il6rafl/fl offspring. Our results demonstrate that IL-6 activation in placenta is required for relaying inflammatory signals to the fetal brain and impacting behaviors and neuropathologies relevant to neurodevelopmental disease.