Aicardi-Goutieres syndrome-like encephalitis in mutant mice with constitutively active MDA5
Aicardi-Goutieres syndrome-like encephalitis in mutant mice with constitutively active MDA5
复制标题
具有组成型活性 MDA5 的突变小鼠中的 Aicardi-Goutieres 综合征样脑炎
DOI：
10.1093/intimm/dxaa073
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发表时间：
2020
影响因子：
4.4
通讯作者：
Fujita Takashi
中科院分区：
文献类型：
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作者：
Onizawa Hideo;Kato Hiroki;Kimura Hiroyuki;Kudo Tomoo;Soda Nobumasa;Shimizu Shota;Funabiki Masahide;Yagi Yusuke;Nakamoto Yuji;Priller Josef;Nishikomori Ryuta;Heike Toshio;Yan Nan;Tsujimura Tohru;Mimori Tsuneyo;Fujita Takashi
MDA 5是病毒RNA的细胞质传感器，触发I型干扰素（IFN-I）的产生。组成型活性MDA 5与自身免疫性疾病有关，如系统性红斑狼疮、Singleton-Merten综合征（SMS）和Aicardi-Goutières综合征（AGS），一种遗传决定的炎性脑病。然而，由于缺乏动物模型，AGS研究具有挑战性。我们先前报道了狼疮样肾炎和SMS样骨异常的成年小鼠组成型活性MDA 5（Ifih 1G 821 S/+），并在此证明，这些小鼠也表现出高致死率和自发性脑炎与高IFN-I生产在出生后早期。以MDA 5/MAVS信号传导和IFN-I依赖的方式观察到小胶质细胞数量的增加。此外，小胶质细胞表现出激活状态，吞噬能力增加，神经营养因子表达减少。尽管在小鼠和AGS患者的血清中检测到多种自身抗体，包括狼疮相关抗体，但Ifih 1G 821 S/+ Rag 2 −/−小鼠也表现出IFN-1、星形胶质细胞增生和小胶质细胞增生的上调，表明脑炎的发展不需要自身抗体或淋巴细胞。在Ifih 1G 821 S/+小鼠中观察到的没有淋巴细胞浸润的IFN-I特征是AGS的典型特征。总的来说，我们的研究结果表明，Ifih 1G 821 S/+小鼠是一种重现AGS的模型，小胶质细胞是AGS治疗的潜在靶点。
MDA5 is a cytoplasmic sensor of viral RNA, triggering type I interferon (IFN-I) production. Constitutively active MDA5 has been linked to autoimmune diseases such as systemic lupus erythematosus, Singleton–Merten syndrome (SMS) and Aicardi–Goutières syndrome (AGS), a genetically determined inflammatory encephalopathy. However, AGS research is challenging due to the lack of animal models. We previously reported lupus-like nephritis and SMS-like bone abnormalities in adult mice with constitutively active MDA5 (Ifih1G821S/+), and herein demonstrate that these mice also exhibit high lethality and spontaneous encephalitis with high IFN-I production during the early postnatal period. Increases in the number of microglia were observed in MDA5/MAVS signaling- and IFN-I-dependent manners. Furthermore, microglia showed an activated state with an increased phagocytic capability and reduced expression of neurotrophic factors. Although multiple auto-antibodies including lupus-related ones were detected in the sera of the mice as well as AGS patients,Ifih1G821S/+Rag2−/−mice also exhibited up-regulation of IFN-I, astrogliosis and microgliosis, indicating that auto-antibodies or lymphocytes are not required for the development of the encephalitis. The IFN-I signature without lymphocytic infiltration observed inIfih1G821S/+mice is a typical feature of AGS. Collectively, our results suggest that theIfih1G821S/+mice are a model recapitulating AGS and that microglia are a potential target for AGS therapy.