DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières syndrome astrocytes
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 pluri...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Rockefeller University Press
2022
|
| _version_ | 1797106874670120960 |
|---|---|
| author | Giordano, AMS Luciani, M Gatto, F Abou Alezz, M Beghè, C Della Volpe, L Migliara, A Valsoni, S Genua, M Dzieciatkowska, M Frati, G Tahraoui-Bories, J Giliani, SC Orcesi, S Fazzi, E Ostuni, R D'Alessandro, A Di Micco, R Merelli, I Lombardo, A Reijns, MAM Gromak, N Gritti, A Kajaste-Rudnitski, A |
| author_facet | Giordano, AMS Luciani, M Gatto, F Abou Alezz, M Beghè, C Della Volpe, L Migliara, A Valsoni, S Genua, M Dzieciatkowska, M Frati, G Tahraoui-Bories, J Giliani, SC Orcesi, S Fazzi, E Ostuni, R D'Alessandro, A Di Micco, R Merelli, I Lombardo, A Reijns, MAM Gromak, N Gritti, A Kajaste-Rudnitski, A |
| author_sort | Giordano, AMS |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T07:08:38Z |
| format | Journal article |
| id | oxford-uuid:035d6d8f-5344-4e48-b3c2-a9aaacf50d43 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:08:38Z |
| publishDate | 2022 |
| publisher | Rockefeller University Press |
| record_format | dspace |
| spelling | oxford-uuid:035d6d8f-5344-4e48-b3c2-a9aaacf50d432022-06-01T14:21:25ZDNA damage contributes to neurotoxic inflammation in Aicardi-Goutières syndrome astrocytesJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:035d6d8f-5344-4e48-b3c2-a9aaacf50d43EnglishSymplectic ElementsRockefeller University Press2022Giordano, AMSLuciani, MGatto, FAbou Alezz, MBeghè, CDella Volpe, LMigliara, AValsoni, SGenua, MDzieciatkowska, MFrati, GTahraoui-Bories, JGiliani, SCOrcesi, SFazzi, EOstuni, RD'Alessandro, ADi Micco, RMerelli, ILombardo, AReijns, MAMGromak, NGritti, AKajaste-Rudnitski, AAberrant 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. |
| spellingShingle | Giordano, AMS Luciani, M Gatto, F Abou Alezz, M Beghè, C Della Volpe, L Migliara, A Valsoni, S Genua, M Dzieciatkowska, M Frati, G Tahraoui-Bories, J Giliani, SC Orcesi, S Fazzi, E Ostuni, R D'Alessandro, A Di Micco, R Merelli, I Lombardo, A Reijns, MAM Gromak, N Gritti, A Kajaste-Rudnitski, A DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières syndrome astrocytes |
| title | DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières syndrome astrocytes |
| title_full | DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières syndrome astrocytes |
| title_fullStr | DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières syndrome astrocytes |
| title_full_unstemmed | DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières syndrome astrocytes |
| title_short | DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières syndrome astrocytes |
| title_sort | dna damage contributes to neurotoxic inflammation in aicardi goutieres syndrome astrocytes |
| work_keys_str_mv | AT giordanoams dnadamagecontributestoneurotoxicinflammationinaicardigoutieressyndromeastrocytes AT lucianim dnadamagecontributestoneurotoxicinflammationinaicardigoutieressyndromeastrocytes AT gattof dnadamagecontributestoneurotoxicinflammationinaicardigoutieressyndromeastrocytes AT aboualezzm dnadamagecontributestoneurotoxicinflammationinaicardigoutieressyndromeastrocytes AT beghec dnadamagecontributestoneurotoxicinflammationinaicardigoutieressyndromeastrocytes AT dellavolpel dnadamagecontributestoneurotoxicinflammationinaicardigoutieressyndromeastrocytes AT migliaraa dnadamagecontributestoneurotoxicinflammationinaicardigoutieressyndromeastrocytes AT valsonis dnadamagecontributestoneurotoxicinflammationinaicardigoutieressyndromeastrocytes AT genuam dnadamagecontributestoneurotoxicinflammationinaicardigoutieressyndromeastrocytes AT dzieciatkowskam dnadamagecontributestoneurotoxicinflammationinaicardigoutieressyndromeastrocytes AT fratig dnadamagecontributestoneurotoxicinflammationinaicardigoutieressyndromeastrocytes AT tahraouiboriesj dnadamagecontributestoneurotoxicinflammationinaicardigoutieressyndromeastrocytes AT gilianisc dnadamagecontributestoneurotoxicinflammationinaicardigoutieressyndromeastrocytes AT orcesis dnadamagecontributestoneurotoxicinflammationinaicardigoutieressyndromeastrocytes AT fazzie dnadamagecontributestoneurotoxicinflammationinaicardigoutieressyndromeastrocytes AT ostunir dnadamagecontributestoneurotoxicinflammationinaicardigoutieressyndromeastrocytes AT dalessandroa dnadamagecontributestoneurotoxicinflammationinaicardigoutieressyndromeastrocytes AT dimiccor dnadamagecontributestoneurotoxicinflammationinaicardigoutieressyndromeastrocytes AT merellii dnadamagecontributestoneurotoxicinflammationinaicardigoutieressyndromeastrocytes AT lombardoa dnadamagecontributestoneurotoxicinflammationinaicardigoutieressyndromeastrocytes AT reijnsmam dnadamagecontributestoneurotoxicinflammationinaicardigoutieressyndromeastrocytes AT gromakn dnadamagecontributestoneurotoxicinflammationinaicardigoutieressyndromeastrocytes AT grittia dnadamagecontributestoneurotoxicinflammationinaicardigoutieressyndromeastrocytes AT kajasterudnitskia dnadamagecontributestoneurotoxicinflammationinaicardigoutieressyndromeastrocytes |