Phenotypic Variation in Aicardi–Goutières Syndrome Explained by Cell-Specific IFN-Stimulated Gene Response and Cytokine Release
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| Title: | Phenotypic Variation in Aicardi–Goutières Syndrome Explained by Cell-Specific IFN-Stimulated Gene Response and Cytokine Release |
|---|---|
| Authors: | Machiel H. Jansen, Lidia De Filippis, Angelo L. Vescovi, Taco W. Kuijpers, Dirk Geerts, Iliana Michailidou, Emma J. van Bodegraven, Elly M. Hol, Pierre-Olivier Couraud, Eloy Cuadrado, Jacqueline A. Sluijs |
| Contributors: | TN groep Hol, Brain |
| Source: | Cuadrado, E, Michailidou, I, van Bodegraven, E J, Jansen, M H, Sluijs, J A, Geerts, D, Couraud, P-O, De Filippis, L, Vescovi, A L, Kuijpers, T W & Hol, E M 2015, 'Phenotypic variation in Aicardi-Goutières syndrome explained by cell-specific IFN-stimulated gene response and cytokine release', Journal of Immunology, vol. 194, no. 8, pp. 3623-33. https://doi.org/10.4049/jimmunol.1401334 |
| Publisher Information: | Oxford University Press (OUP), 2015. |
| Publication Year: | 2015 |
| Subject Terms: | 0301 basic medicine, Astrocytes/immunology, Exodeoxyribonucleases/genetics, Autoimmune Diseases of the Nervous System/genetics, Adenosine Deaminase, Interferon-alpha/genetics, Immunology, Ribonuclease H, Nervous System Malformations, Monomeric GTP-Binding Proteins/genetics, SAM Domain and HD Domain-Containing Protein 1, 03 medical and health sciences, Autoimmune Diseases of the Nervous System, Neural Stem Cells, Phosphoproteins/genetics, Taverne, Neural Stem Cells/immunology, Journal Article, Humans, Gene Silencing, Monomeric GTP-Binding Proteins, 0303 health sciences, Cytokines/genetics, Research Support, Non-U.S. Gov't, Endothelial Cells/immunology, Endothelial Cells, Interferon-alpha, RNA-Binding Proteins, Ribonuclease H/genetics, EMC MM-02-54-03, Phosphoproteins, RNA-Binding Proteins/genetics, 3. Good health, Exodeoxyribonucleases, HEK293 Cells, Astrocytes, Cytokines, Mutation, Adenosine Deaminase/genetics, Nervous System Malformations/genetics |
| Description: | 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. |
| Document Type: | Article |
| File Description: | application/pdf |
| Language: | English |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.1401334 |
| Access URL: | https://www.jimmunol.org/content/jimmunol/194/8/3623.full.pdf https://pubmed.ncbi.nlm.nih.gov/25769924 https://europepmc.org/abstract/MED/25769924 http://www.jimmunol.org/lookup/doi/10.4049/jimmunol.1401334 https://repub.eur.nl/pub/84282 https://www.ncbi.nlm.nih.gov/pubmed/25769924 https://pure.knaw.nl/ws/files/2109943/Cuadrado2015JImmunol.pdf https://moh-it.pure.elsevier.com/en/publications/phenotypic-variation-in-aicardi-gouti%C3%A8res-syndrome-explained-by-c https://research.vumc.nl/en/publications/efa4e71f-d194-4310-aa85-d083d3aa5da9 https://dspace.library.uu.nl/handle/1874/331333 |
| Rights: | OUP Standard Publication Reuse |
| Accession Number: | edsair.doi.dedup.....7859f877f1e001ea52a4445bf5ad6eb0 |
| Database: | OpenAIRE |
Nájsť tento článok vo Web of Science | 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. |
|---|---|
| ISSN: | 15506606 00221767 |
| DOI: | 10.4049/jimmunol.1401334 |