Phenotypic Variation in Aicardi–Goutières Syndrome Explained by Cell-Specific IFN-Stimulated Gene Response and Cytokine Release

摘要: Aicardi-Goutieres syndrome (AGS) is a monogenic inflammatory encephalopathy caused by mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, or MDA5. Mutations those genes affect normal RNA/DNA intracellular metabolism and detection, triggering an autoimmune response with increase cerebral IFN-α production astrocytes. Microangiopathy vascular disease also contribute to the neuropathology AGS. In this study, we report that AGS gene silencing of ADAR1 short hairpin RNAs human neural stem cell-derived astrocytes, primary brain-derived endothelial cells leads antiviral status these compared nontarget RNA-treated cells. We observed distinct activation IFN-stimulated signature substantial release proinflammatory cytokines (IL-6) chemokines (CXCL10 CCL5). A differential impact was noted; TREX1 gave rise most dramatic both cell types. Our findings fit well observation patients carrying experience earlier onset fatal outcome. provide present our knowledge for first time, insight into how astrocytic may differentially lead pathology, suggesting rational link between mediators severity