• Eloy Cuadrado, Iliana Michailidou, Emma J van Bodegraven, Machiel H Jansen, Jacqueline A Sluijs, Dirk Geerts, Pierre-Olivier Couraud, Lidia De Filippis, Angelo L Vescovi, Taco W Kuijpers, and Elly M Hol.
• 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; eloycua@gmail.com.
• J. Immunol. 2015 Apr 15;194(8):3623-33.

AbstractAicardi-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.Copyright © 2015 by The American Association of Immunologists, Inc.

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