Cuadrado Eloy, Michailidou Iliana, van Bodegraven Emma J, Jansen Machiel H, Sluijs Jacqueline A, Geerts Dirk, Couraud Pierre-Olivier, De Filippis Lidia, Vescovi Angelo L, Kuijpers Taco W, Hol Elly M
Department of Astrocyte Biology and Neurodegeneration, Netherlands Institute for Neuroscience, Institute of the Royal Netherlands Academy of Arts and Sciences, 1105 BA Amsterdam, the Netherlands; Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands;
Department of Genome Analysis, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands;
J Immunol. 2015 Apr 15;194(8):3623-33. doi: 10.4049/jimmunol.1401334. Epub 2015 Mar 13.
Aicardi-Goutières syndrome (AGS) is a monogenic inflammatory encephalopathy caused by mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, or MDA5. Mutations in those genes affect normal RNA/DNA intracellular metabolism and detection, triggering an autoimmune response with an increase in cerebral IFN-α production by astrocytes. Microangiopathy and vascular disease also contribute to the neuropathology in AGS. In this study, we report that AGS gene silencing of TREX1, SAMHD1, RNASEH2A, and ADAR1 by short hairpin RNAs in human neural stem cell-derived astrocytes, human primary astrocytes, and brain-derived endothelial cells leads to an antiviral status of these cells compared with nontarget short hairpin RNA-treated cells. We observed a distinct activation of the IFN-stimulated gene signature with a substantial increase in the release of proinflammatory cytokines (IL-6) and chemokines (CXCL10 and CCL5). A differential impact of AGS gene silencing was noted; silencing TREX1 gave rise to the most dramatic in both cell types. Our findings fit well with the observation that patients carrying mutations in TREX1 experience an earlier onset and fatal outcome. We provide in the present study, to our knowledge for the first time, insight into how astrocytic and endothelial activation of antiviral status may differentially lead to cerebral pathology, suggesting a rational link between proinflammatory mediators and disease severity in AGS.
艾卡迪-古铁雷斯综合征（AGS）是一种单基因炎症性脑病，由TREX1、RNASEH2A、RNASEH2B、RNASEH2C、SAMHD1、ADAR1或MDA5基因突变引起。这些基因的突变影响正常的RNA/DNA细胞内代谢和检测，引发自身免疫反应，导致星形胶质细胞产生的脑内干扰素-α增加。微血管病变和血管疾病也参与了AGS的神经病理学过程。在本研究中，我们报告称，在人神经干细胞来源的星形胶质细胞、人原代星形胶质细胞和脑源性内皮细胞中，通过短发夹RNA对TREX1、SAMHD1、RNASEH2A和ADAR1进行AGS基因沉默，与非靶向短发夹RNA处理的细胞相比，会使这些细胞进入抗病毒状态。我们观察到干扰素刺激基因特征明显激活，促炎细胞因子（IL-6）和趋化因子（CXCL10和CCL5）的释放大幅增加。注意到AGS基因沉默有不同的影响；在两种细胞类型中，沉默TREX1产生的影响最为显著。我们的发现与以下观察结果非常吻合：携带TREX1突变的患者发病更早且预后不良。据我们所知，本研究首次深入了解了星形胶质细胞和内皮细胞的抗病毒状态激活如何不同地导致脑部病变，提示了促炎介质与AGS疾病严重程度之间的合理联系。
