RNase H2 Loss in Murine Astrocytes Results in Cellular Defects Reminiscent of Nucleic Acid-Mediated Autoinflammation.
RNase H2 Loss in Murine Astrocytes Results in Cellular Defects Reminiscent of Nucleic Acid-Mediated Autoinflammation.
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DOI：
10.3389/fimmu.2018.00587
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发表时间：
2018
影响因子：
7.3
通讯作者：
Rabe B
中科院分区：
文献类型：
--
作者：
Bartsch K;Damme M;Regen T;Becker L;Garrett L;Hölter SM;Knittler K;Borowski C;Waisman A;Glatzel M;Fuchs H;Gailus-Durner V;Hrabe de Angelis M;Rabe B
Aicardi-Goutières 综合征 (AGS) 是一种罕见的早发性儿童脑病，由自身免疫源性持续性神经炎症引起。 AGS 是一种遗传性疾病，超过 50% 的受影响个体携带核糖核酸酶 H2 (RNase H2) 低等位突变。迄今为止，所有可用的 RNase H2 小鼠模型都无法模仿 AGS 中所见的突出的中枢神经系统受累。为了建立重现人类疾病的小鼠模型，我们专门删除了大脑中的 RNase H2，大脑是 AGS 中受影响最严重的器官。尽管 RNase H2ΔGFAP 小鼠星形胶质细胞和大多数神经元中缺乏核酸酶，但这些动物没有明显的疾病迹象。我们还在第二个神经元特异性 RNase H2 敲除小鼠品系中证实了这些结果。然而，当从 RNase H2ΔGFAP 小鼠的大脑中分离出星形胶质细胞并在促有丝分裂条件下培养时，它们表现出 DNA 损伤和过早衰老的迹象。干扰素刺激基因 (ISG) 的表达增强是最可靠的 AGS 生物标志物。重要的是，原代 RNase H2ΔGFAP 星形胶质细胞显示出显着增加的 ISG 转录水平，但我们未能在 RNase H2ΔGFAP 小鼠大脑中体内检测到这一水平。因 DNA 损伤（包括 RNase H2 缺陷）而引发的分离星形胶质细胞，在暴露于细菌或病毒抗原时表现出增强的先天免疫反应。总之，我们建立了一个有效的细胞 AGS 模型，该模型利用负责疾病病理学的细胞类型——星形胶质细胞，并复制在 AGS 患者细胞中观察到的主要分子缺陷。
Aicardi–Goutières syndrome (AGS) is a rare early onset childhood encephalopathy caused by persistent neuroinflammation of autoimmune origin. AGS is a genetic disorder and >50% of affected individuals bear hypomorphic mutations in ribonuclease H2 (RNase H2). All available RNase H2 mouse models so far fail to mimic the prominent CNS involvement seen in AGS. To establish a mouse model recapitulating the human disease, we deleted RNase H2 specifically in the brain, the most severely affected organ in AGS. Although RNase H2ΔGFAP mice lacked the nuclease in astrocytes and a majority of neurons, no disease signs were apparent in these animals. We additionally confirmed these results in a second, neuron-specific RNase H2 knockout mouse line. However, when astrocytes were isolated from brains of RNase H2ΔGFAP mice and cultured under mitogenic conditions, they showed signs of DNA damage and premature senescence. Enhanced expression of interferon-stimulated genes (ISGs) represents the most reliable AGS biomarker. Importantly, primary RNase H2ΔGFAP astrocytes displayed significantly increased ISG transcript levels, which we failed to detect in in vivo in brains of RNase H2ΔGFAP mice. Isolated astrocytes primed by DNA damage, including RNase H2-deficiency, exhibited a heightened innate immune response when exposed to bacterial or viral antigens. Taken together, we established a valid cellular AGS model that utilizes the very cell type responsible for disease pathology, the astrocyte, and phenocopies major molecular defects observed in AGS patient cells.
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影响因子：
32.4
作者：
Gall A;Treuting P;Elkon KB;Loo YM;Gale M Jr;Barber GN;Stetson DB
通讯作者：
Stetson DB
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
4
作者：
Ponting, C;Jackson, AP
通讯作者：
Jackson, AP
影响因子：
25
作者：
Madisen L;Zwingman TA;Sunkin SM;Oh SW;Zariwala HA;Gu H;Ng LL;Palmiter RD;Hawrylycz MJ;Jones AR;Lein ES;Zeng H
通讯作者：
Zeng H
DOI：
10.1084/jem.20120876
发表时间：
2012-07-30
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hiller B;Achleitner M;Glage S;Naumann R;Behrendt R;Roers A
通讯作者：
Roers A