Astroglial IFITM3 mediates neuronal impairments following neonatal immune challenge in mice
Astroglial IFITM3 mediates neuronal impairments following neonatal immune challenge in mice
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DOI：
10.1002/glia.22461
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发表时间：
2013-05-01
期刊：
影响因子：
6.2
通讯作者：
Yamada, Kiyofumi
中科院分区：
文献类型：
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作者：
Ibi, Daisuke;Nagai, Taku;Yamada, Kiyofumi
干扰素诱导的跨膜蛋白3(IFITM3)在I型干扰素(IFN)的抗病毒反应中起重要作用。然而，尽管IFITM3在神经系统和神经精神疾病患者的大脑中表达增加，但它在中枢神经系统(CNS)中的作用在很大程度上是未知的。在这里，我们展示了IFITM3在发育早期多聚核苷-多核糖核酸(PolyI：C，一种合成双链RNA)诱导的免疫挑战后长期神经元损伤中的作用。我们发现，用PolyI：C处理的小鼠脑内IFITM3的表达仅在星形胶质细胞中观察到。培养的星形胶质细胞被PolyI：C激活，导致炎性细胞因子和IFITM3的mRNA水平增加。用PolyI：C处理的星形胶质细胞条件培养液(PolyI：C-ACM)处理培养的神经元时，轴突发育受到损害。IFITM3/星形胶质细胞条件培养液可减轻PolyI：C-ACM诱导的神经发育异常。此外，在接受PolyI：C治疗的野生型小鼠中，MAP2的表达、棘突密度、额叶皮质的树突复杂性以及记忆障碍都明显降低，但在IFITM3/小鼠中没有观察到这样的神经元损伤。我们还发现，在PolyI：C处理后，IFITM3蛋白定位于星形胶质细胞的早期内吞体内，并降低了内吞活性。这些发现表明，在发育早期，通过激活先天免疫系统在星形胶质细胞中诱导IFITM3的表达具有非细胞自主效应，影响随后的神经发育，通过损害星形胶质细胞的内吞作用，导致神经病理损伤和脑功能障碍。Glia 2013
Interferon-induced transmembrane protein 3 (IFITM3) plays a crucial role in the antiviral responses of Type I interferons (IFNs). The role of IFITM3 in the central nervous system (CNS) is, however, largely unknown, despite the fact that its expression is increased in the brains of patients with neurologic and neuropsychiatric diseases. Here, we show the role of IFITM3 in long-lasting neuronal impairments in mice following polyriboinosinic-polyribocytidylic acid (polyI:C, a synthetic double-stranded RNA)-induced immune challenge during the early stages of development. We found that the induction of IFITM3 expression in the brain of mice treated with polyI:C was observed only in astrocytes. Cultured astrocytes were activated by polyI:C treatment, leading to an increase in the mRNA levels of inflammatory cytokines as well as Ifitm3. When cultured neurons were treated with the conditioned medium of polyI:C-treated astrocytes (polyI:C-ACM), neurite development was impaired. These polyI:C-ACM-induced neurodevelopmental abnormalities were alleviated by ifitm3/ astrocyte-conditioned medium. Furthermore, decreases of MAP2 expression, spine density, and dendrite complexity in the frontal cortex as well as memory impairment were evident in polyI:C-treated wild-type mice, but such neuronal impairments were not observed in ifitm3/ mice. We also found that IFITM3 proteins were localized to the early endosomes of astrocytes following polyI:C treatment and reduced endocytic activity. These findings suggest that the induction of IFITM3 expression in astrocytes by the activation of the innate immune system during the early stages of development has non-cell autonomous effects that affect subsequent neurodevelopment, leading to neuropathological impairments and brain dysfunction, by impairing endocytosis in astrocytes. GLIA 2013