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

J Immunol. 2015 Apr 15;194(8):3623-33. doi: 10.4049/jimmunol.1401334. Epub 2015 Mar 13.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Deaminase / genetics
  • Adenosine Deaminase / immunology
  • Astrocytes / immunology*
  • Astrocytes / pathology
  • Autoimmune Diseases of the Nervous System / genetics
  • Autoimmune Diseases of the Nervous System / immunology*
  • Autoimmune Diseases of the Nervous System / mortality
  • Autoimmune Diseases of the Nervous System / pathology
  • Cytokines / genetics
  • Cytokines / immunology*
  • Endothelial Cells / immunology*
  • Endothelial Cells / pathology
  • Exodeoxyribonucleases / genetics
  • Exodeoxyribonucleases / immunology
  • Gene Silencing
  • HEK293 Cells
  • Humans
  • Interferon-alpha / genetics
  • Interferon-alpha / immunology*
  • Monomeric GTP-Binding Proteins / genetics
  • Monomeric GTP-Binding Proteins / immunology
  • Mutation
  • Nervous System Malformations / genetics
  • Nervous System Malformations / immunology*
  • Nervous System Malformations / mortality
  • Nervous System Malformations / pathology
  • Neural Stem Cells / immunology*
  • Neural Stem Cells / pathology
  • Phosphoproteins / genetics
  • Phosphoproteins / immunology
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / immunology
  • Ribonuclease H / genetics
  • Ribonuclease H / immunology
  • SAM Domain and HD Domain-Containing Protein 1


  • Cytokines
  • Interferon-alpha
  • Phosphoproteins
  • RNA-Binding Proteins
  • Exodeoxyribonucleases
  • three prime repair exonuclease 1
  • ribonuclease HII
  • Ribonuclease H
  • SAM Domain and HD Domain-Containing Protein 1
  • SAMHD1 protein, human
  • ADAR protein, human
  • Adenosine Deaminase
  • Monomeric GTP-Binding Proteins

Supplementary concepts

  • Aicardi-Goutieres syndrome