Chronic exposure of astrocytes to interferon-α reveals molecular changes related to Aicardi-Goutieres syndrome.
Brain
; 136(Pt 1): 245-58, 2013 Jan.
Article
em En
| MEDLINE
| ID: mdl-23365100
ABSTRACT
Aicardi-Goutières syndrome is a genetically determined infantile encephalopathy, manifesting as progressive microcephaly, psychomotor retardation, and in â¼25% 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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Astrócitos
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Interferon-alfa
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Doenças Autoimunes do Sistema Nervoso
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Malformações do Sistema Nervoso
Tipo de estudo:
Prognostic_studies
Limite:
Adolescent
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Adult
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Aged80
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Child
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Child, preschool
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Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article