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Peptidylarginine deiminase 4 (PAD4), a critical enzyme for NET formation, is also significantly upregulated in the ischemic brains of tPA-treated mice. Blood\u2013brain barrier (BBB) disruption after ischemic challenge in an in vitro model of BBB was exacerbated after exposure to NETs. Importantly, disruption of NETs by DNase I or inhibition of NET production by PAD4 deficiency restored tPA-induced loss of BBB integrity and consequently decreased tPA-associated brain hemorrhage after ischemic stroke. Furthermore, either DNase I or PAD4 deficiency reversed tPA-mediated upregulation of the DNA sensor cyclic GMP-AMP (cGAMP) synthase (cGAS). Administration of cGAMP after stroke abolished DNase I\u2013mediated downregulation of the STING pathway and type 1 interferon production and blocked the antihemorrhagic effect of DNase I in tPA-treated mice. We also show that tPA-associated brain hemorrhage after ischemic stroke was significantly reduced in cGas\u2212\/\u2212 mice. Collectively, these findings demonstrate that NETs significantly contribute to tPA-induced BBB breakdown in the ischemic brain and suggest that targeting NETs or cGAS may ameliorate thrombolytic therapy for ischemic stroke by reducing tPA-associated hemorrhage.<\/jats:p>","DOI":"10.1182\/blood.2020008913","type":"journal-article","created":{"date-parts":[[2021,4,21]],"date-time":"2021-04-21T18:19:47Z","timestamp":1619029187000},"page":"91-103","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":241,"title":["Neutrophil extracellular traps promote tPA-induced brain hemorrhage via cGAS in mice with stroke"],"prefix":"10.1182","volume":"138","author":[{"given":"Ranran","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Translational Neuroscience, Jing\u2019an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology\u2013Ministry of Education (MOE) Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanbo","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Translational Neuroscience, Jing\u2019an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology\u2013Ministry of Education (MOE) Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongwang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Translational Neuroscience, Jing\u2019an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology\u2013Ministry of Education (MOE) Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, 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