Phenotypic variation in Aicardi-Goutières syndrome explained by cell-specific IFN-stimulated gene response and cytokine release

The Journal of Immunology : Official Journal of the American Association of Immunologists
Eloy CuadradoElly M Hol

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 ti...Continue Reading

References

Apr 1, 1988·Journal of the Neurological Sciences·P LebonJ Aicardi
Aug 12, 1999·Acta Neuropathologica·P G BarthI van Gelderen
Jan 1, 2003·Clinical Chemistry·Robert AuerbachNasim Akhtar
Aug 19, 2003·The Anatomical Record. Part A, Discoveries in Molecular, Cellular, and Evolutionary Biology·Shan-Zheng YangFeng-Yan Sun
Nov 14, 2003·The Journal of Biological Chemistry·Qingde WangKazuko Nishikura
Apr 13, 2004·Proceedings of the National Academy of Sciences of the United States of America·Andrew I SuJohn B Hogenesch
Jul 16, 2004·Molecular and Cellular Biology·Masashi MoritaDeborah E Barnes
Aug 25, 2006·Nature Methods·David E RootDavid M Sabatini
Aug 30, 2008·Cell·Daniel B StetsonRuslan Medzhitov
Jul 27, 2010·Developmental Medicine and Child Neurology·Venkateswaran RameshYanick J Crow
Mar 16, 2011·Proceedings of the National Academy of Sciences of the United States of America·Baozhong XinHeng Wang
Jun 3, 2011·Proceedings of the National Academy of Sciences of the United States of America·Marcel du MoulinFrank Rutsch
Jul 18, 2012·The Journal of Experimental Medicine·Bjoern HillerAxel Roers
Aug 21, 2012·The Journal of Immunology : Official Journal of the American Association of Immunologists·Christine M SesteroChander Raman
Jan 22, 2013·Journal of Neuropathology and Experimental Neurology·Joost SmoldersInge Huitinga
Feb 15, 2013·Neurology·Asako TakanohashiAdeline Vanderver
Jul 17, 2013·Proceedings of the National Academy of Sciences of the United States of America·Elisa FranzolinVera Bianchi
Jul 23, 2013·The EMBO Journal·Jan RehwinkelCaetano Reis e Sousa
Nov 13, 2013·The Journal of Immunology : Official Journal of the American Association of Immunologists·Selma Pereira-LopesAntonio Celada
Jan 22, 2014·Annals of the Rheumatic Diseases·Stefanie KretschmerMin Ae Lee-Kirsch

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Citations

Sep 2, 2015·Blood·Selma Pereira-LopesAntonio Celada
Aug 26, 2015·Nature Reviews. Neurology·Sarah McGlassonDavid Hunt
Apr 27, 2017·Reviews in Medical Virology·Miaomiao LiJun Li
May 10, 2018·Brain Pathology·Sunetra SaseAkshata Almad
Jun 21, 2019·Protein Science : a Publication of the Protein Society·L Therese BergendahlJoseph A Marsh
Feb 24, 2016·The EMBO Journal·Karen J MackenzieAndrew P Jackson
Jan 11, 2020·Annals of Clinical and Translational Neurology·Jeffrey LambeArun Venkatesan
Nov 9, 2016·The Journal of Experimental Medicine·Mathieu P Rodero, Yanick J Crow
Oct 19, 2017·Scientific Reports·Maria PujantellEster Ballana
Sep 7, 2018·Clinical Science·Fiona Moghaddas, Seth L Masters
Jan 24, 2021·Pediatric Rheumatology Online Journal·Tingyan HeJun Yang
Nov 25, 2020·Seminars in Cell & Developmental Biology·Taylor A Evans, Jennifer Ann Erwin
Apr 17, 2021·Scientific Reports·Isabella BattenNollaig M Bourke
Apr 20, 2021·Frontiers in Pediatrics·Debora M d'AngeloFrancesco Chiarelli
Jul 3, 2021·International Journal of Molecular Sciences·Giulia Di DonatoFrancesco Chiarelli

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