Novel insights into double-stranded RNA-mediated immunopathology.
Journal
Nature reviews. Immunology
ISSN: 1474-1741
Titre abrégé: Nat Rev Immunol
Pays: England
ID NLM: 101124169
Informations de publication
Date de publication:
26 Sep 2023
26 Sep 2023
Historique:
accepted:
24
08
2023
medline:
27
9
2023
pubmed:
27
9
2023
entrez:
26
9
2023
Statut:
aheadofprint
Résumé
Recent progress in human and mouse genetics has transformed our understanding of the molecular mechanisms by which recognition of self double-stranded RNA (self-dsRNA) causes immunopathology. Novel mouse models recapitulate loss-of-function mutations in the RNA editing enzyme ADAR1 that are found in patients with Aicardi-Goutières syndrome (AGS) - a monogenic inflammatory disease associated with increased levels of type I interferon. Extensive analyses of the genotype-phenotype relationships in these mice have now firmly established a causal relationship between increased intracellular concentrations of endogenous immunostimulatory dsRNA and type I interferon-driven immunopathology. Activation of the dsRNA-specific immune sensor MDA5 perpetuates the overproduction of type I interferons, and chronic engagement of the interferon-inducible innate immune receptors PKR and ZBP1 by dsRNA drives immunopathology by activating an integrated stress response or by inducing excessive cell death. Biochemical and genetic data support a role for the p150 isoform of ADAR1 in the cytosol in suppressing the spontaneous, pathological response to self-dsRNA.
Identifiants
pubmed: 37752355
doi: 10.1038/s41577-023-00940-3
pii: 10.1038/s41577-023-00940-3
doi:
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2023. Springer Nature Limited.
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