Astrocytes produce interferon‐alpha and CXCL10, but not IL‐6 or CXCL8, in aicardi‐Goutières syndrome

Abstract

Aicardi-Goutières syndrome (AGS) presents as a severe autosomal recessively inherited neurological brain disease. Clinical and neurological manifestations closely resemble those of congenital viral infection and are generally attributed to a perturbation of innate immunity including a long lasting lymphocytosis and production of interferon-alpha (IFNalpha) in the central nervous system. To clarify the innate immune response evoked in these diseases, we used a 30-mer multiplexed luminex system to measure multiple cytokines and growth factors in the cerebrospinal fluid and serum of patients with AGS and viral meningitis or encephalitis, and febrile controls in whom infection could not be substantiated. In addition to the previously described IFNalpha, both AGS and viral diseases were characterized by expression of CXCL10 and CCL2. In contrast to AGS, viral infection resulted in high levels of IL-6 and CXCL8 in the CNS. Postmortem immunohistochemical staining of brain sections showed that in both AGS and viral CNS infection, astrocytes were responsible for the production of cytokines and not the infiltrating leukocytes. In summary, our data indicate that astrocytes are the predominant cell type responsible for the production of IFNalpha and CXCL10 in AGS. Whereas IFNalpha is assumed to be involved in the neurodegeneration, calcifications and seizures in AGS, CXCL10 may act as the chemoattractant responsible for the influx of activated lymphocytes into the brain. The lack of the inflammatory cytokines IL-6 and CXCL8 in AGS suggest that the neuroinflammatory reaction in this disease is distinct from viral disease.

Phenotypic Variation in Aicardi–Goutières Syndrome Explained by Cell-Specific IFN-Stimulated Gene Response and Cytokine Release

“…Even though IFN-a is considered to be a key biomarker for AGS, the chemokine CXCL10 has also been persistently demonstrated to have an elevated expression in AGS patients (12,13). Consistent with this, our study shows that silencing AGS genes results in an increased expression and release of CXCL10 mainly in astrocytes.…”

“…IFN-a is a wellknown potent antiangiogenic factor and is therefore used as coadjuvant therapy in different types of cancer (44). Second, the levels of IFN-a remain sustainably high for years in both serum and CSF (12,45). Third, a general downregulation of angiogenesis-related genes has been described for AGS patients carrying different genotypes (46).…”

“…Our group has identified astrocytes as the major source of this IFN-a. These are also responsible for the increase in chemokines, such as CXCL10, in the brain of AGS patients (12). AGS patients also present elevated CSF levels of FMS-related tyrosine kinase 3 ligand, IL-12p40, IL-15, TNF-a, and soluble IL-2 receptor (13).…”

Characterization of samhd1 Morphant Zebrafish Recapitulates Features of the Human Type I Interferonopathy Aicardi-Goutières Syndrome

“…Functional knowledge of the zebrafish specific chemokine cxc46 is relatively poor. However, other CXC chemokine family members are upregulated in response to viral infection in zebrafish larvae (18), and increased expression of chemokines has been reported in AGS (42,43). Increased expression of genes encoding the transcription factors irf1b, irf7, stat1b, and cebpb, as observed in our morphants, has also been recorded following exposure to two viruses in zebrafish infection models (18), and significant upregulation of the human orthologs, STAT1 and IRF7 is seen in AGS (7).…”

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.…”