DNA-sensing inflammasomes cause recurrent atherosclerotic stroke

• 成果类型: Article
• 署名作者: Cao, Jiayu; Roth, Stefan; Zhang, Sijia; Kopczak, Anna; Mami, Samira; Asare, Yaw; Georgakis, Marios K.; Messerer, Denise; Horn, Amit; Shemer, Ruth; Jacqmarcq, Charlene; Picot, Audrey; Green, Jack P.; Schlegl, Christina; Li, Xinghai; Tomas, Lukas; Dutsch, Alexander; Liman, Thomas G.; Endres, Matthias; Wernsdorf, Saskia R.; Fuerle, Christina; Carofiglio, Olga; Zhu, Jie; Brough, David; Hornung, Veit; Dichgans, Martin; Vivien, Denis; Schulz, Christian; Dor, Yuval; Tiedt, Steffen; Sager, Hendrik B.; Grosse, Gerrit M.; Liesz, Arthur
• 署名单位: University of Munich; University of Munich; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; University of Munich; Hebrew University of Jerusalem; Universite de Caen Normandie; Institut National de la Sante et de la Recherche Medicale (Inserm); University of Manchester; Technical University of Munich; German Heart Centre Munich; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; German Centre for Cardiovascular Research; University of Munich; University of Munich; German Centre for Cardiovascular Research; Munich Heart Alliance; Helmholtz Association; German Center for Neurodegenerative Diseases (DZNE); CHU de Caen NORMANDIE; Universite de Caen Normandie; Ruprecht Karls University Heidelberg; Hannover Medical School
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5122
• DOI: 10.1038/s41586-024-07803-4
• 发表日期: 2024-09-12
• 页码: 433-+
• 关键词: ischemic-stroke; myocardial-infarction; RISK; instability; mouse

摘要

The risk of early recurrent events after stroke remains high despite currently established secondary prevention strategies(1). Risk is particularly high in patients with atherosclerosis, with more than 10% of patients experiencing early recurrent events(1,2). However, despite the enormous medical burden of this clinical phenomenon, the underlying mechanisms leading to increased vascular risk and recurrent stroke are largely unknown. Here, using a novel mouse model of stroke-induced recurrent ischaemia, we show that stroke leads to activation of the AIM2 inflammasome in vulnerable atherosclerotic plaques via an increase of circulating cell-free DNA. Enhanced plaque inflammation post-stroke results in plaque destabilization and atherothrombosis, finally leading to arterioarterial embolism and recurrent stroke within days after the index stroke. We confirm key steps of plaque destabilization also after experimental myocardial infarction and in carotid artery plaque samples from patients with acute stroke. Rapid neutrophil NETosis was identified as the main source of cell-free DNA after stroke and NET-DNA as the causative agent leading to AIM2 inflammasome activation. Neutralization of cell-free DNA by DNase treatment or inhibition of inflammasome activation reduced the rate of stroke recurrence after experimental stroke. Our findings present an explanation for the high recurrence rate after incident ischaemic events in patients with atherosclerosis. The detailed mechanisms uncovered here provide clinically uncharted therapeutic targets for which we show high efficacy to prevent recurrent events. Targeting DNA-mediated inflammasome activation after remote tissue injury represents a promising avenue for further clinical development in the prevention of early recurrent events.