title: Phenotypic variation in Aicardi-Goutières syndrome explained by cell-specific IFN-stimulated gene response and cytokine release.
abstract: 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.
authors.affiliation: 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.
authors.forename: Eloy
authors.initials: E
authors.lastname: Cuadrado
authors.affiliation: Department of Genome Analysis, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands;
authors.forename: Iliana
authors.initials: I
authors.lastname: Michailidou
authors.affiliation: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3584 CG Utrecht, the Netherlands;
authors.forename: Emma J
authors.initials: EJ
authors.lastname: van Bodegraven
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands;
authors.forename: Machiel H
authors.initials: MH
authors.lastname: Jansen
authors.affiliation: 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 Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3584 CG Utrecht, the Netherlands;
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Sluijs
authors.affiliation: Department of Pediatric Oncology, Erasmus Medical Center, 3015 CN Rotterdam, the Netherlands;
authors.forename: Dirk
authors.initials: D
authors.lastname: Geerts
authors.affiliation: Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Institut Cochin, Université Paris Descartes, INSERM, Paris 75014, France;
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Couraud
authors.affiliation: Dipartimento di Biotecnologie e Bioscienze, Università degli Studi di Milano-Bicocca, Milan 20126, Italy; and.
authors.forename: Lidia
authors.initials: L
authors.lastname: De Filippis
authors.affiliation: Dipartimento di Biotecnologie e Bioscienze, Università degli Studi di Milano-Bicocca, Milan 20126, Italy; and.
authors.forename: Angelo L
authors.initials: AL
authors.lastname: Vescovi
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands;
authors.forename: Taco W
authors.initials: TW
authors.lastname: Kuijpers
authors.affiliation: 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 Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3584 CG Utrecht, the Netherlands; Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, 1098 XH Amsterdam, the Netherlands.
authors.forename: Elly M
authors.initials: EM
authors.lastname: Hol
mesh_terms: D000243:Adenosine Deaminase / Q000235:genetics / Q000276:immunology; D001253:Astrocytes / Q000276:immunology* / Q000473:pathology; D020274:Autoimmune Diseases of the Nervous System / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000276:immunology*; D042783:Endothelial Cells / Q000276:immunology* / Q000473:pathology; D005090:Exodeoxyribonucleases / Q000235:genetics / Q000276:immunology; D020868:Gene Silencing; D057809:HEK293 Cells; D006801:Humans; D016898:Interferon-alpha / Q000235:genetics / Q000276:immunology*; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000276:immunology; D009154:Mutation; D009421:Nervous System Malformations / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D058953:Neural Stem Cells / Q000276:immunology* / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics / Q000276:immunology; D016601:RNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D016914:Ribonuclease H / Q000235:genetics / Q000276:immunology; D000076106:SAM Domain and HD Domain-Containing Protein 1
chemical_list: D016207:Cytokines; D016898:Interferon-alpha; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D005090:Exodeoxyribonucleases; C429526:three prime repair exonuclease 1; C091139:ribonuclease HII; D016914:Ribonuclease H; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; C000595356:ADAR protein, human; D000243:Adenosine Deaminase; D020559:Monomeric GTP-Binding Proteins