Maternal Type-I interferon signaling adversely affects the microglia and the behavior of the offspring accompanied by increased sensitivity to stress
Maternal Type-I interferon signaling adversely affects the microglia and the behavior of the offspring accompanied by increased sensitivity to stress
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DOI：
10.1038/s41380-019-0604-0
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发表时间：
2020-05-01
影响因子：
11
通讯作者：
Schwartz, Michal
中科院分区：
文献类型：
--
作者：
Ben-Yehuda, Hila;Matcovitch-Natan, Orit;Schwartz, Michal
怀孕期间的病毒感染通常与神经精神疾病有关。在小鼠中，将妊娠母鼠暴露于病毒模拟物poly（I：C），通过称为母体免疫激活（MIA）的过程，作为模拟后代中这种病理学的模型。为了研究这种效应的机制，我们假设母体上调I型干扰素（IFN-I），作为母体抗病毒反应的一部分，可能会导致对后代的损害。使用mRNA测序和流式细胞术分析，我们发现，在怀孕期间，聚（I：C）治疗引起的后代的小胶质细胞相对于对照组的增殖和细胞周期相关的基因的表达减少。这被发现与胚胎卵黄囊中的IFN-I信号相关，卵黄囊是发育中小胶质细胞的起源。在母鼠中中和IFN-I信号减弱了MIA对新生儿小胶质细胞的影响，而全身性母体给予IFN β足以模拟poly（I：C）的作用，并导致后代小胶质细胞对随后压力的脆弱性增加。此外，母体IFN β升高导致神经精神疾病的行为表现。此外，通过采用“两击”的实验范式，我们显示了更高的敏感性的后代出生后的压力，母亲的IFN β升高，表现出行为的不规则性。我们的研究结果表明，母亲上调IFN-I，在MIA的反应，干扰后代的编程小胶质细胞的发展级联，增加他们对产后压力的易感性，并导致行为异常。
Viral infection during pregnancy is often associated with neuropsychiatric conditions. In mice, exposure of pregnant dams to the viral mimetic poly(I:C), serves as a model that simulates such pathology in the offspring, through a process known as Maternal Immune Activation (MIA). To investigate the mechanism of such effect, we hypothesized that maternal upregulation of Type-I interferon (IFN-I), as part of the dam's antiviral response, might contribute to the damage imposed on the offspring. Using mRNA sequencing and flow cytometry analyses we found that poly(I:C) treatment during pregnancy caused reduced expression of genes related to proliferation and cell cycle in the offspring's microglia relative to controls. This was found to be associated with an IFN-I signature in the embryonic yolk sac, the origin of microglia in development. Neutralizing IFN-I signaling in dams attenuated the effect of MIA on the newborn's microglia, while systemic maternal administration of IFN beta was sufficient to mimic the effect of poly(I:C), and led to increased vulnerability of offspring's microglia to subsequent stress. Furthermore, maternal elevation of IFN beta resulted in behavioral manifestations reminiscent of neuropsychiatric disorders. In addition, by adopting a "two-hit" experimental paradigm, we show a higher sensitivity of the offspring to postnatal stress subsequent to the maternal IFN beta elevation, demonstrated by behavioral irregularities. Our results suggest that maternal upregulation of IFN-I, in response to MIA, interferes with the offspring's programmed microglial developmental cascade, increases their susceptibility to postnatal stress, and leads to behavioral abnormalities.