DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières syndrome astrocytes
Anna M. Giordano, Marco Luciani, Francesca Gatto, Monah Abou Alezz, Chiara Beghè, Lucrezia della Volpe, Alessandro Migliara, Sara Valsoni, Marco Genua, Monika Dzieciątkowska, Giacomo Frati, Julie Tahraoui‐Bories, Silvia Giliani, Simona Orcesi, Elisa Fazzi, Renato Ostuni, Angelo D’Alessandro, Raffaella Di Micco, Ivan Merelli, Angelo Lombardo, Martin A.M. Reijns, Natalia Gromak, Angela Gritti, Anna Kajaste‐Rudnitski
Abstract
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.