Zdroj: |
Giordano, A M S, Luciani, M, Gatto, F, Alezz, M A, Beghè, C, Volpe, L D, Migliara, A, Valsoni, S, Genua, M, Dzieciatkowska, M, Frati, G, Tahraoui-Bories, J, Giliani, S, Orcesi, S, Fazzi, E, Ostuni, R, D'Alessandro, A, Di Micco, R, Merelli, I, Lombardo, A, Reijns, M A M, Gromak, N, Gritti, A & Kajaste-Rudnitski, A 2022, ' DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières Syndrome astrocytes ', Journal of Experimental Medicine . https://doi.org/10.1084/jem.20211121 |
Popis: |
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. |