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.

Ribonuclease H2 mutations induce a cGAS/STING‐dependent innate immune response

“…Upregulation of both transcripts was confirmed by RT–qPCR, and ELISA of culture supernatants from all six Rnaseh2b −/− lines demonstrated significantly increased CCL5 and CXCL10 secretion (Fig 3D and E, and Appendix Fig S2B). Notably, these cytokines have previously been implicated in AGS neuroinflammation in humans (van Heteren et al , 2008; Takanohashi et al , 2013; Cuadrado et al , 2015). We therefore concluded that impaired RNase H2 activity in vitro and in vivo results in a similar inflammatory response to that observed in patients with AGS, and like for Trex1 deficiency (Gall et al , 2012) is present in non‐immune cells.…”

NBS1 is required for macrophage homeostasis and functional activity in mice

“…52,53 We recently reported enhanced proinflammatory activation in macrophages from mice lacking Trex1, 22 and the release of cytokines has been attributed to phenotypic variations in patients with Aicardi-Goutières syndrome. 54 Mutations that lead to activation of innate immunity by inducing the secretion of type I IFN collectively may represent "interferonopathies", 55 disorders that are characterized by neurologic and dermatologic features provoked by autoimmunity.…”

Late diagnosis and atypical brain imaging of Aicardi–Goutières syndrome: are we failing to diagnose Aicardi–Goutières syndrome‐2?

“…Some patients with AGS exhibit later onset of symptoms, and lack abnormalities on brain imaging or CSF . Numerous patients with RNASEH2B mutations and AGS type 2 (AGS2) have a milder phenotype with lower childhood mortality and better preservation of function .…”