Adult behavioral and pharmacological dysfunctions following disruption of the fetal brain balance between pro-inflammatory and IL-10-mediated anti-inflammatory signaling
Adult behavioral and pharmacological dysfunctions following disruption of the fetal brain balance between pro-inflammatory and IL-10-mediated anti-inflammatory signaling
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DOI：
10.1038/sj.mp.4002042
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发表时间：
2008-02-01
影响因子：
11
通讯作者：
Feldon, J.
中科院分区：
文献类型：
--
作者：
Meyer, U.;Murray, P. J.;Feldon, J.
母亲在怀孕期间的感染增加了后代患精神分裂症和假定神经发育起源的相关疾病的风险。这种关联已被归因于促炎细胞因子在胎儿环境中响应于母体免疫刺激的表达增强。相反，在这种情况下，抗炎细胞因子的具体作用几乎是未知的。在这里，我们证明，基因强制表达的抗炎细胞因子白细胞介素（IL）-10的巨噬细胞减弱产前免疫激活的长期行为和药理学后果的产前病毒样感染的小鼠模型，由聚核糖肌苷酸-聚核糖胞苷酸（聚：C; 2毫克/公斤，静脉注射）。然而，在缺乏离散的产前炎症刺激的情况下，母胎界面IL-10水平的提高本身也会使成年后代出现特定的行为异常。这突出表明，除了过量促炎分子的破坏性作用外，产前生活中向增强抗炎信号传导的转变也会同样影响认知和行为发育。因此，促炎和抗炎细胞因子类别之间的平衡的转变可能是对生命早期感染或先天免疫失衡后神经发育的最终影响的关键决定因素。
Maternal infections during pregnancy increase the risk for schizophrenia and related disorders of putative neurodevelopmental origin in the offspring. This association has been attributed to enhanced expression of pro-inflammatory cytokines in the fetal environment in response to maternal immunological stimulation. In contrast, the specific roles of anti-inflammatory cytokines are virtually unknown in this context. Here, we demonstrate that genetically enforced expression of the anti-inflammatory cytokine interleukin (IL)-10 by macrophages attenuates the long-term behavioral and pharmacological consequences of prenatal immune activation in a mouse model of prenatal viral-like infection by polyriboinosinic-polyribocytidilic acid (Polyl:C; 2 mg/kg, intravenously). In the absence of a discrete prenatal inflammatory stimulus, however, enhanced levels of IL-10 at the maternal-fetal interface by itself also precipitates specific behavioral abnormalities in the grown offspring. This highlights that in addition to the disruptive effects of excess pro-inflammatory molecules, a shift toward enhanced anti-inflammatory signaling in prenatal life can similarly affect cognitive and behavioral development. Hence, shifts of the balance between pro- and anti-inflammatory cytokine classes may be a critical determinant of the final impact on neurodevelopment following early life infection or innate immune imbalances.