Maternal immune activation with staphylococcal enterotoxin A produces unique behavioral changes in C57BL/6 mouse offspring
Maternal immune activation with staphylococcal enterotoxin A produces unique behavioral changes in C57BL/6 mouse offspring
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DOI：
10.1016/j.bbi.2018.05.005
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发表时间：
2019-01-01
影响因子：
15.1
通讯作者：
Kusnecov, Alexander W.
中科院分区：
文献类型：
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作者：
Glass, Ruthy;Norton, Sara;Kusnecov, Alexander W.
怀孕期间免疫系统的刺激，称为母体免疫激活（MIA），可导致后代长期的神经生物学和行为变化。这种现象与自闭症和精神分裂症等发育性精神障碍的病因有关。大部分证据都是基于使用细菌制剂（如LPS）和/或病毒模拟物（如Poly I：C）的动物模型，两者都通过Toll样受体发挥作用。然而，很少有研究探讨在怀孕期间使用微生物制剂直接激活母体T细胞的作用。细菌超抗原，如葡萄球菌肠毒素A和B（SEA; SE B），是激活CD 4 T细胞并引起显著的T细胞增殖和细胞因子产生的微生物蛋白。我们用200 μ g/Kg的SEA、SEB或0.9%盐水注射怀孕和未怀孕的成年雌性C57 BL/6小鼠，并测量脾T细胞衍生的细胞因子浓度（即，IL-2、IFN-γ、IL-6和IL-4）;还测量了注射SEA的动物的TNF α和IL-17 A的脾浓度。半数注射的妊娠动物足月分娩，从6周龄（出生后第42天[P42]）开始对它们的后代进行一系列行为任务测试。这些任务包括社会互动，高架十字迷宫（ESTA），一个开放的领域和对象识别（OR）的任务，前脉冲抑制（PPI）的感觉运动门控，和莫里斯水迷宫（MWM）。结果显示，SEA和SEB诱导显著浓度的所有测量的细胞因子，特别是IFN-γ，尽管细胞因子应答在SEA暴露后更大。此外，妊娠诱导细胞因子的产生抑制作用。行为结果显示，不同的表型之间的后代从SEA或SEB注射的母亲，很可能是由于在响应于每种毒素产生的细胞因子的幅度的差异。SEA注射的母亲的后代表现出适度的社会行为减少，但增加了焦虑，运动，对新物体的兴趣和短期空间记忆，而SEB注射的母亲的后代只表现出增加的焦虑和运动。PPI没有缺陷，这在SEA和SEB后代中实际上是明显的。总体而言，SEA和SEB作为产前免疫挑战的新用途在后代中引起了不同的行为特征，这些行为特征在重要方面既反映了先前的母体免疫激活模型，又与之前的模型不同。我们的结论是，超抗原诱导的T细胞介导的母体免疫激活是一个有效的和有价值的模型，研究和扩大我们的理解产前免疫挑战对后代的神经发育和行为改变的影响。
Stimulation of the immune system during pregnancy, known as maternal immune activation (MIA), can cause long-lasting neurobiological and behavioral changes in the offspring. This phenomenon has been implicated in the etiology of developmental psychiatric disorders, such as autism and schizophrenia. Much of this evidence is predicated on animal models using bacterial agents such as LPS and/or viral mimics such as Poly I:C, both of which act through toll-like receptors. However, fewer studies have examined the role of direct activation of maternal T-cells during pregnancy using microbial agents. Bacterial superantigens, such as Staphylococcal Enterotoxin A and B (SEA; SEB), are microbial proteins that activate CD4 T-cells and cause prominent T-cell proliferation and cytokine production. We injected pregnant and non-pregnant adult female C57BL/6 mice with 200 g/Kg of SEA, SEB, or 0.9% saline, and measured splenic T-cell-derived cytokine concentrations (viz., IL-2, IFN-gamma, IL-6, and IL-4) 2 h later; animals injected with SEA were also measured for splenic concentrations of TNF alpha and IL-17A. Half of the injected pregnant animals were brought to term, and their offspring were tested on a series of behavioral tasks starting at six weeks of age (postnatal day 42 [P42]). These tasks included social interaction, the elevated plus maze (EPM), an open field and object recognition (OR) task, prepulse inhibition (PPI) of sensorimotor gating, and the Morris water maze (MWM). Results showed that SEA and SEB induced significant concentrations of all measured cytokines, and in particular IFN-gamma, although cytokine responses were greater following SEA exposure. In addition, pregnancy induced an inhibitory effect on cytokine production. Behavioral results showed distinct phenotypes among offspring from SEA- or SEB-injected mothers, very likely due to differences in the magnitude of cytokines generated in response to each toxin. Offspring from SEA injected mothers displayed modest decreases in social behavior, but increased anxiety, locomotion, interest in a novel object, and short-term spatial memory, while offspring of SEB-injected mothers only exhibited increased anxiety and locomotion. There were no deficits in PPI, which was actually pronounced in SEA and SEB offspring. Overall, the novel use of SEA and SEB as prenatal immune challenges elicited distinct behavioral profiles in the offspring that both mirrors and diverges from previous models of maternal immune activation in important ways. We conclude that superantigen-induced T-cell-mediated maternal immune activation is a valid and valuable model for studying and expanding our understanding of the effects of prenatal immune challenge on neurodevelopmental and behavioral alterations in offspring.