Chronic exposure of astrocytes to interferon-α reveals molecular changes related to Aicardi-Goutieres syndrome.
Aicardi-Goutières syndrome is a genetically determined infantile encephalopathy, manifesting as progressive microcephaly, psychomotor retardation, and in ∼25% of patients, death in early childhood. Aicardi-Goutières 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-α production. Astrocytes have been identified as a major source of interferon-α production in the brains of patients with Aicardi-Goutières syndrome. Here, we study the effect of interferon-α treatment on astrocytes derived from immortalized human neural stem cells. Chronic interferon-α 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, eIF2Bα, 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-α for 7 days barely reversed these cellular alterations, demonstrating that the interferon-α mediated effects persist over time. We confirmed our in vitro findings using brain samples from patients with Aicardi-Goutières syndrome. Our results support the idea of interferon-α as a key factor in the pathogenesis of Aicardi-Goutières syndrome relating to the observed leukodystrophy and microangiopathy. Because of the sustained interferon-α effect, even after withdrawal, therapeutic targets for Aicardi-Goutières syndrome, and other interferon-α-mediated encephalopathies, may include downstream interferon-α signalling cascade effectors rather than interferon-α alone.
Department of Astrocyte Biology and Neurodegeneration, Netherlands Institute for Neuroscience–an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands. e.cuadrado@nin.knaw.nl
Eloy
E
Cuadrado
Machiel H
MH
Jansen
Jasper
J
Anink
Lidia
L
De Filippis
Angelo L
AL
Vescovi
Colin
C
Watts
Eleonora
E
Aronica
Elly M
EM
Hol
Taco W
TW
Kuijpers
D000293:Adolescent; D000328:Adult; D000369:Aged, 80 and over; D001253:Astrocytes / Q000187:drug effects* / Q000276:immunology; D020274:Autoimmune Diseases of the Nervous System / Q000235:genetics* / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D005911:Gliosis / Q000276:immunology; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D008297:Male; D009421:Nervous System Malformations / Q000235:genetics* / Q000276:immunology; D058953:Neural Stem Cells / Q000187:drug effects / Q000276:immunology
D016898:Interferon-alpha