DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières syndrome astrocytes.
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
04 04 2022
04 04 2022
Historique:
received:
22
05
2021
revised:
22
11
2021
accepted:
24
01
2022
entrez:
9
3
2022
pubmed:
10
3
2022
medline:
3
5
2022
Statut:
ppublish
Résumé
Aberrant induction of type I IFN is a hallmark of the inherited encephalopathy Aicardi-Goutières syndrome (AGS), but the mechanisms triggering disease in the human central nervous system (CNS) remain elusive. Here, we generated human models of AGS using genetically modified and patient-derived pluripotent stem cells harboring TREX1 or RNASEH2B loss-of-function alleles. Genome-wide transcriptomic analysis reveals that spontaneous proinflammatory activation in AGS astrocytes initiates signaling cascades impacting multiple CNS cell subsets analyzed at the single-cell level. We identify accumulating DNA damage, with elevated R-loop and micronuclei formation, as a driver of STING- and NLRP3-related inflammatory responses leading to the secretion of neurotoxic mediators. Importantly, pharmacological inhibition of proapoptotic or inflammatory cascades in AGS astrocytes prevents neurotoxicity without apparent impact on their increased type I IFN responses. Together, our work identifies DNA damage as a major driver of neurotoxic inflammation in AGS astrocytes, suggests a role for AGS gene products in R-loop homeostasis, and identifies common denominators of disease that can be targeted to prevent astrocyte-mediated neurotoxicity in AGS.
Identifiants
pubmed: 35262626
pii: 213058
doi: 10.1084/jem.20211121
pmc: PMC8916121
pii:
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Medical Research Council
ID : MC_UU_00007/5
Pays : United Kingdom
Organisme : Telethon
Pays : Italy
Informations de copyright
© 2022 Giordano et al.
Déclaration de conflit d'intérêts
Disclosures: A. D’Alessandro reported “other” from Omix Technologies Inc, personal fees from Hemanext Inc., and personal fees from Forma Therapeutics outside the submitted work. No other disclosures were reported.
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