DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières syndrome astrocytes.
DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières syndrome astrocytes.
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DOI：
10.1084/jem.20211121
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发表时间：
2022-04-04
期刊：
影响因子：
--
通讯作者：
Kajaste-Rudnitski A
中科院分区：
文献类型：
--
作者：
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
Giordano等人建立了TREX1或RNASEH2B缺陷的人类AGS ipsc模型。他们发现DNA损伤是AGS星形胶质细胞神经毒性炎症的主要驱动因素，可以从异常的I型IFN反应中解耦，并确定了减少AGS神经炎症的新靶点。I型IFN的异常诱导是遗传性脑病aicardii - gouti<e:1>综合征（AGS）的一个标志，但在人类中枢神经系统（CNS）中引发疾病的机制尚不清楚。在这里，我们使用含有TREX1或RNASEH2B功能缺失等位基因的转基因和患者来源的多能干细胞生成了AGS的人类模型。全基因组转录组学分析显示，AGS星形胶质细胞的自发促炎激活启动了影响单细胞水平分析的多个CNS细胞亚群的信号级联反应。我们发现累积的DNA损伤，随着r环和微核形成的升高，是STING和nlrp3相关炎症反应的驱动因素，导致神经毒性介质的分泌。重要的是，AGS星形胶质细胞的促凋亡或炎症级联的药理抑制可以防止神经毒性，而不会明显影响其增加的I型IFN反应。总之，我们的工作确定了DNA损伤是AGS星形胶质细胞神经毒性炎症的主要驱动因素，表明AGS基因产物在r -环稳态中的作用，并确定了可以靶向预防AGS星形胶质细胞介导的神经毒性的疾病的共同特征。
Giordano et al. establish human AGS iPSC-based models of TREX1 or RNASEH2B deficiencies. They uncover DNA damage as a major driver of neurotoxic inflammation in AGS astrocytes that can be uncoupled from aberrant type I IFN responses and identify novel targets to curtail AGS neuroinflammation. 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.
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影响因子：
13.6
作者：
Chatzidoukaki O;Stratigi K;Goulielmaki E;Niotis G;Akalestou-Clocher A;Gkirtzimanaki K;Zafeiropoulos A;Altmüller J;Topalis P;Garinis GA
通讯作者：
Garinis GA
DOI：
10.1073/pnas.1507125112
发表时间：
2015-06-09
影响因子：
11.1
作者：
Darmanis S;Sloan SA;Zhang Y;Enge M;Caneda C;Shuer LM;Hayden Gephart MG;Barres BA;Quake SR
通讯作者：
Quake SR
影响因子：
16.2
作者：
Aditi;Downing SM;Schreiner PA;Kwak YD;Li Y;Shaw TI;Russell HR;McKinnon PJ
通讯作者：
McKinnon PJ
在Aicardi-Goutières综合征中突变的RNase H2促进了LINE-1逆转录位。
DOI：
10.15252/embj.201798506
发表时间：
2018-08-01
期刊：
The EMBO journal
影响因子：
--
作者：
Benitez-Guijarro M;Lopez-Ruiz C;Tarnauskaitė Ž;Murina O;Mian Mohammad M;Williams TC;Fluteau A;Sanchez L;Vilar-Astasio R;Garcia-Canadas M;Cano D;Kempen MH;Sanchez-Pozo A;Heras SR;Jackson AP;Reijns MA;Garcia-Perez JL
通讯作者：
Garcia-Perez JL
影响因子：
2
作者：
Crow, Yanick J.;Chase, Diana S.;Schmidt, Johanna Lowenstein;Szynkiewicz, Marcin;Forte, Gabriella M. A.;Gornall, Hannah L.;Oojageer, Anthony;Anderson, Beverley;Pizzino, Amy;Helman, Guy;Abdel-Hamid, Mohamed S.;Abdel-Salam, Ghada M.;Ackroyd, Sam;Aeby, Alec;Agosta, Guillermo;Albin, Catherine;Allon-Shalev, Stavit;Arellano, Montse;Ariaudo, Giada;Aswani, Vijay;Babul-Hirji, Riyana;Baildam, Eileen M.;Bahi-Buisson, Nadia;Bailey, Kathryn M.;Barnerias, Christine;Barth, Magalie;Battini, Roberta;Beresford, Michael W.;Bernard, Genevieve;Bianchi, Marika;de Villemeur, Thierry Billette;Blair, Edward M.;Bloom, Miriam;Burlina, Alberto B.;Carpanelli, Maria Luisa;Carvalho, Daniel R.;Castro-Gago, Manuel;Cavallini, Anna;Cereda, Cristina;Chandler, Kate E.;Chitayat, David A.;Collins, Abigail E.;Sierra Corcoles, Concepcion;Cordeiro, Nuno J. V.;Crichiutti, Giovanni;Dabydeen, Lyvia;Dale, Russell C.;D'Arrigo, Stefano;De Goede, Christian G. E. L.;De Laet, Corinne;De Waele, Liesbeth M. H.;Denzler, Ines;Desguerre, Isabelle;Devriendt, Koenraad;Di Rocco, Maja;Fahey, Michael C.;Fazzi, Elisa;Ferrie, Colin D.;Figueiredo, Antonio;Gener, Blanca;Goizet, Cyril;Gowrinathan, Nirmala R.;Gowrishankar, Kalpana;Hanrahan, Donncha;Isidor, Bertrand;Kara, Lent;Khan, Nasaim;King, Mary D.;Kirk, Edwin P.;Kumar, Ram;Lagae, Lieven;Landrieu, Pierre;Lauffer, Heinz;Laugel, Vincent;La Piana, Roberta;Lim, Ming J.;Lin, Jean-Pierre S. -M.;Linnankivi, Tarja;Mackay, Mark T.;Marom, Daphna R.;Lourenco, Charles Marques;McKee, Shane A.;Moroni, Isabella;Morton, Jenny E. V.;Moutard, Marie-Laure;Murray, Kevin;Nabbout, Rima;Nampoothiri, Sheela;Nunez-Enamorado, Noemi;Oades, Patrick J.;Olivieri, Ivana;Ostergaard, John R.;Perez-Duenas, Belen;Prendiville, Julie S.;Ramesh, Venkateswaran;Rasmussen, Magnhild;Regal, Luc;Ricci, Federica;Rio, Marlene;Rodriguez, Diana;Roubertie, Agathe;Salvatici, Elisabetta;Segers, Karin A.;Sinha, Gyanranjan P.;Soler, Doriette;Spiegel, Ronen;Stoedberg, Tommy I.;Straussberg, Rachel;Swoboda, Kathryn J.;Suri, Mohnish;Tacke, Uta;Tan, Tiong Y.;Naude, Johann te Water;Teik, Keng Wee;Thomas, Maya Mary;Till, Marianne;Tonduti, Davide;Valente, Enza Maria;Van Coster, Rudy Noel;van der Knaap, Marjo S.;Vassallo, Grace;Vijzelaar, Raymon;Vogt, Julie;Wallace, Geoffrey B.;Wassmer, Evangeline;Webb, Hannah J.;Whitehouse, William P.;Whitney, Robyn N.;Zaki, Maha S.;Zuberi, Sameer M.;Livingston, John H.;Rozenberg, Flore;Lebon, Pierre;Vanderver, Adeline;Orcesi, Simona;Rice, Gillian I.
通讯作者：
Rice, Gillian I.