Innate immune activation of astrocytes impairs neurodevelopment via upregulation of follistatin-like 1 and interferon-induced transmembrane protein 3.
Innate immune activation of astrocytes impairs neurodevelopment via upregulation of follistatin-like 1 and interferon-induced transmembrane protein 3.
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DOI：
10.1186/s12974-018-1332-0
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发表时间：
2018-10-22
影响因子：
9.3
通讯作者：
Yamada K
中科院分区：
文献类型：
--
作者：
Yamada S;Itoh N;Nagai T;Nakai T;Ibi D;Nakajima A;Nabeshima T;Yamada K
多聚核糖核糖核酸(PolyI：C)可激发强烈的先天免疫反应，模拟病毒感染引起的免疫激活。干扰素诱导的星形胶质细胞跨膜蛋白3(IFITM3)的诱导在PolyI：C诱导的神经发育异常中起着关键作用。通过定量蛋白质组学筛选，我们先前在Polyl：C诱导的神经发育障碍中确定了候选星形胶质细胞因子，如基质金属蛋白酶-3(MMP3)和卵泡抑素样蛋白1(FSTL1)。在这里，我们描述了在PolyI：C治疗后，以星形胶质细胞来源的FSTL1为重点的IFITM3依赖的炎症过程，以评估FSTL1的神经病理作用。用PBS(对照组)或PolyI：C(10μg/mL)处理星形胶质细胞。在PolyI：C处理后24小时收集条件培养液作为星形胶质细胞条件培养液(ACM)。用定量聚合酶链式反应和Western blotting分别检测FSTL1mRNA和胞外FSTL1蛋白的表达水平。在功能研究方面，用ACM处理神经元，并分析ACM对树突延长的影响。为了研究FSTL1的作用，采用重组FSTL1蛋白和针对FSTL1的siRNA。为了研究FSTL1在体内的表达，新生小鼠在出生后第2~6天分别给予赋形剂或PolyI：C处理。用PolyI：C制备的ACM(PolyI：C ACM)的FSTL1蛋白含量显著高于对照组ACM，但从IFITM3缺陷的星形胶质细胞来源的PolyI：C ACM中FSTL1的表达没有增加。我们发现，FSTL1的产生涉及星形胶质细胞中的炎症反应分子IFITM3，并影响神经元的分化。与之一致的是，PolyI：C处理的新生小鼠的海马区FSTL1水平增加。FSTL1和IFITM3联合转染组的COS7细胞胞外FSTL1表达水平高于单独转染组。用重组FSTL1处理原代培养的海马神经元可损害树突状细胞的伸长，而PolyI：C ACM对树突伸长的有害作用可通过敲除星形胶质细胞中的FSTL1而减弱。星形胶质细胞中FSTL1的胞外水平受IFITM3的调节，可能参与了PolyI：C诱导的神经发育障碍。本文的在线版本(10.1186/s12974-0181332-0)包含向授权用户提供的补充材料。
Polyriboinosinic-polyribocytidylic acid (polyI:C) triggers a strong innate immune response that mimics immune activation by viral infections. Induction of interferon-induced transmembrane protein 3 (Ifitm3) in astrocytes has a crucial role in polyI:C-induced neurodevelopmental abnormalities. Through a quantitative proteomic screen, we previously identified candidate astroglial factors, such as matrix metalloproteinase-3 (Mmp3) and follistatin-like 1 (Fstl1), in polyl:C-induced neurodevelopmental impairment. Here, we characterized the Ifitm3-dependent inflammatory processes focusing on astrocyte-derived Fstl1 following polyI:C treatment to assess the neuropathologic role of Fstl1. Astrocytes were treated with PBS (control) or polyI:C (10 μg/mL). The conditioned medium was collected 24 h after the polyI:C treatment and used as astrocyte condition medium (ACM). The expression of Fstl1 mRNA and extracellular Fstl1 protein levels were analyzed by quantitative PCR and western blotting, respectively. For functional studies, neurons were treated with ACM and the effects of ACM on dendritic elongation were assayed. To examine the role of Fstl1, recombinant Fstl1 protein and siRNA for Fstl1 were used. To investigate the expression of Fstl1 in vivo, neonatal mice were treated with vehicle or polyI:C on postnatal day 2 to 6. ACM prepared with polyI:C (polyI:C ACM) contained significantly higher Fstl1 protein than control ACM, but no increase in Fstl1 was observed in polyI:C ACM derived from Ifitm3-deficient astrocytes. We found that the production of Fstl1 involves the inflammatory responsive molecule Ifitm3 in astrocytes and influences neuronal differentiation. In agreement, the levels of Fstl1 increased in the hippocampus of polyI:C-treated neonatal mice. COS7 cells co-transfected with both Fstl1 and Ifitm3 had higher extracellular levels of Fstl1 than the cells transfected with Fstl1 alone. Treatment of primary cultured hippocampal neurons with recombinant Fstl1 impaired dendritic elongation, and the deleterious effect of polyI:C ACM on dendritic elongation was attenuated by knockdown of Fstl1 in astrocytes. The extracellular level of Fstl1 is regulated by Ifitm3 in astrocytes, which could be involved in polyI:C-induced neurodevelopmental impairment. The online version of this article (10.1186/s12974-018-1332-0) contains supplementary material, which is available to authorized users.
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