Department of Medical Microbiology and Immunology, University of California, Davis, Davis, CA, USA.
The M.I.N.D. Institute, University of California at Sacramento, Sacramento, CA, USA.
J Neuroinflammation. 2024 May 7;21(1):118. doi: 10.1186/s12974-024-03106-7.
Maternal inflammation during gestation is associated with a later diagnosis of neurodevelopmental disorders including autism spectrum disorder (ASD). However, the specific impact of maternal immune activation (MIA) on placental and fetal brain development remains insufficiently understood. This study aimed to investigate the effects of MIA by analyzing placental and brain tissues obtained from the offspring of pregnant C57BL/6 dams exposed to polyinosinic: polycytidylic acid (poly I: C) on embryonic day 12.5. Cytokine and mRNA content in the placenta and brain tissues were assessed using multiplex cytokine assays and bulk-RNA sequencing on embryonic day 17.5. In the placenta, male MIA offspring exhibited higher levels of GM-CSF, IL-6, TNFα, and LT-α, but there were no differences in female MIA offspring. Furthermore, differentially expressed genes (DEG) in the placental tissues of MIA offspring were found to be enriched in processes related to synaptic vesicles and neuronal development. Placental mRNA from male and female MIA offspring were both enriched in synaptic and neuronal development terms, whereas females were also enriched for terms related to excitatory and inhibitory signaling. In the fetal brain of MIA offspring, increased levels of IL-28B and IL-25 were observed with male MIA offspring and increased levels of LT-α were observed in the female offspring. Notably, we identified few stable MIA fetal brain DEG, with no male specific difference whereas females had DEG related to immune cytokine signaling. Overall, these findings support the hypothesis that MIA contributes to the sex- specific abnormalities observed in ASD, possibly through altered neuron developed from exposure to inflammatory cytokines. Future research should aim to investigate how interactions between the placenta and fetal brain contribute to altered neuronal development in the context of MIA.
母体妊娠期间的炎症与神经发育障碍（包括自闭症谱系障碍）的后期诊断有关。然而，母体免疫激活（MIA）对胎盘和胎儿大脑发育的具体影响仍知之甚少。本研究旨在通过分析孕 C57BL/6 母鼠暴露于聚肌苷酸：聚胞苷酸（poly I: C）后胚胎第 12.5 天的胎盘中获得的组织，来研究 MIA 的影响。使用多重细胞因子分析和胚胎第 17.5 天的 bulk-RNA 测序来评估胎盘和脑组织中的细胞因子和 mRNA 含量。在胎盘组织中，雄性 MIA 后代表现出更高水平的 GM-CSF、IL-6、TNFα 和 LT-α，但雌性 MIA 后代没有差异。此外，还发现 MIA 后代胎盘组织中的差异表达基因（DEG）富集在与突触小泡和神经元发育相关的过程中。雄性和雌性 MIA 后代的胎盘 mRNA 均富集在突触和神经元发育相关术语中，而雌性后代还富集在兴奋性和抑制性信号相关术语中。在 MIA 后代的胎脑中，观察到雄性 MIA 后代的 IL-28B 和 IL-25 水平升高，而雌性后代的 LT-α 水平升高。值得注意的是，我们仅鉴定到少数稳定的 MIA 胎脑 DEG，雄性中没有特定差异，而雌性中与免疫细胞因子信号相关的 DEG。总体而言，这些发现支持了 MIA 导致 ASD 中观察到的性别特异性异常的假说，这可能是通过暴露于炎症细胞因子导致发育中的神经元发生改变。未来的研究应旨在探讨胎盘和胎儿大脑之间的相互作用如何在 MIA 背景下导致神经元发育改变。
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