The Suppression of Maternal–Fetal Leukemia Inhibitory Factor Signal Relay Pathway by Maternal Immune Activation Impairs Brain Development in Mice

Recent studies in rodents suggest that maternal immune activation (MIA) by viral infection is associated with schizophrenia and autism in offspring. Although maternal IL-6 is though t to be a possible mediator relating MIA induced these neuropsychiatric disorders, the mechanism remains to be elucidated. Previously, we reported that the maternal leukemia inhibitory factor (LIF)–placental ACTH–fetal LIF signaling relay pathway (maternal–fetal LIF signal relay) promotes neurogenesis of fetal cerebrum in rats. Here we report that the maternal–fetal LIF signal relay in mice is suppressed by injection of polyriboinosinic-polyribocytidylic acid into dams, which induces MIA at 12.5 days post-coitum. Maternal IL-6 levels and gene expression of placental suppressor of cytokine signaling 3 (Socs3) increased according to the severity of MIA and gene expression of placental Socs3 correlated with maternal IL-6 levels. Furthermore, we show that MIA causes reduction of LIF level in the fetal cerebrospinal fluid, resulting in the decreased neurogenesis in the cerebrum. These findings suggest that maternal IL-6 interferes the maternal–fetal LIF signal relay by inducing SOCS3 in the placenta and leads to decreased neurogenesis.

近期针对啮齿类动物的研究显示，病毒感染诱发的母体免疫激活（maternal immune activation, MIA）与子代精神分裂症及孤独症的发病密切相关。尽管学界推测母体白细胞介素-6（interleukin-6, IL-6）可能是介导母体免疫激活引发此类神经精神疾病的关键因子，但其具体作用机制仍有待阐明。此前本团队的研究证实，大鼠体内存在母体白血病抑制因子（leukemia inhibitory factor, LIF）-胎盘促肾上腺皮质激素（placental ACTH）-胎儿LIF信号传导通路（简称母胎LIF信号轴），该通路可促进胎儿大脑的神经发生过程。本研究发现，在小鼠妊娠第12.5天对母鼠注射聚肌苷酸-聚胞苷酸（polyriboinosinic-polyribocytidylic acid）可诱导母体免疫激活，进而抑制母胎LIF信号轴。进一步分析显示，随着母体免疫激活程度加重，母体内IL-6水平及胎盘细胞因子信号抑制因子3（suppressor of cytokine signaling 3, Socs3）的基因表达均显著上调，且胎盘Socs3的基因表达水平与母体IL-6水平呈显著正相关。此外，本研究证实母体免疫激活会导致胎儿脑脊液中LIF水平降低，进而引发胎儿大脑神经发生水平下降。上述研究结果表明，母体IL-6可通过诱导胎盘中SOCS3的表达，干扰母胎LIF信号轴，最终导致胎儿大脑神经发生受损。