Chronic exposure of astrocytes to interferon-α reveals molecular changes related to Aicardi-Goutieres syndrome

Aicardi-Goutieres syndrome is a genetically determined infantile encephalopathy, manifesting as progressive microcephaly, psychomotor retardation, and in similar to 25% of patients, death in early childhood. Aicardi-Goutieres syndrome is caused by mutations in any of the genes encoding TREX1, RNASEH2-A, -B, -C and SAMHD1, with protein dysfunction hypothesized to result in the accumulation of nucleic acids within the cell, thus triggering an autoinflammatory response with increased interferon-alpha production. Astrocytes have been identified as a major source of interferon-alpha production in the brains of patients with Aicardi-Goutieres syndrome. Here, we study the effect of interferon-alpha treatment on astrocytes derived from immortalized human neural stem cells. Chronic interferon-alpha treatment promoted astrocyte activation and a reduction in cell proliferation. Moreover, chronic exposure resulted in an alteration of genes and proteins involved in the stability of white matter (ATF4, eIF2B alpha, cathepsin D, cystatin F), an increase of antigen-presenting genes (human leukocyte antigen class I) and downregulation of pro-angiogenic factors and other cytokines (vascular endothelial growth factor and IL-1). Interestingly, withdrawal of interferon-alpha for 7 days barely reversed these cellular alterations, demonstrating that the interferon-alpha mediated effects persist over time. We confirmed our in vitro findings using brain samples from patients with Aicardi-Goutieres syndrome. Our results support the idea of interferon-alpha as a key factor in the pathogenesis of Aicardi-Goutieres syndrome relating to the observed leukodystrophy and microangiopathy. Because of the sustained interferon-alpha effect, even after withdrawal, therapeutic targets for Aicardi-Goutieres syndrome, and other interferon-alpha-mediated encephalopathies, may include downstream interferon-alpha signalling cascade effectors rather than interferon-alpha alone.