Translational evidence suggests that cytokines involved in maternal immune activation (MIA), such as interleukin-6 (IL-6) and interferon-γ (IFN-γ), can cross the placenta, injure fetal brain, and predispose to neuropsychiatric disorders. To elaborate developmental neuronal sequelae of MIA, we differentiated human pluripotent stem cells to cortical neurons over a two-month period, exposing them to IL-6 or IFN-γ. IL-6 impacted expression of genes regulating extracellular matrix, actin cytoskeleton and TGF-β signaling while IFN-γ impacted genes regulating antigen processing, major histocompatibility complex and endoplasmic reticulum biology. IL-6, but not IFN-γ, altered mitochondrial respiration while IFN-γ, but not IL-6, induced reduction in dendritic spine density. Pre-treatment with folic acid, which has known neuroprotective and anti-inflammatory properties, ameliorated IL-6 effects on mitochondrial respiration and IFN-γ effects on dendritic spine density. These findings suggest distinct mechanisms for how fetal IL-6 and IFN-γ exposure influence risk for neuropsychiatric disorders, and how folic acid can mitigate such risk.

转化证据表明，参与母体免疫激活 (MIA) 的细胞因子，例如白细胞介素 6 (IL-6) 和干扰素 γ (IFN-γ)，可以穿过胎盘、损伤胎儿大脑并诱发神经精神疾病。为了详细说明 MIA 的发育神经元后遗症，我们在两个月的时间内将人类多能干细胞分化为皮质神经元，并将它们暴露于 IL-6 或 IFN-γ。IL-6影响调节细胞外基质、肌动蛋白细胞骨架和TGF-β信号传导的基因的表达，而IFN-γ影响调节抗原加工、主要组织相容性复合体和内质网生物学的基因。IL-6（而非 IFN-γ）改变线粒体呼吸，而 IFN-γ（而非 IL-6）诱导树突棘密度降低。叶酸预处理，它具有已知的神经保护和抗炎特性，改善 IL-6 对线粒体呼吸的影响以及 IFN-γ 对树突棘密度的影响。这些发现表明胎儿 IL-6 和 IFN-γ 暴露如何影响神经精神疾病风险以及叶酸如何减轻此类风险的不同机制。