von Jule Filler ; Marios K. Georgakis ; Daniel Janowitz ; Marco Düring ; Rong Fang ; Anna Dewenter ; Felix J. Bode ; Sebastian Stösser ; Christine Kindler ; Peter Hermann ; Christian H. Nolte ; Thomas Liman ; Lucia Kerti ; Kathleen Bernkopf ; Benno Ikenberg ; Wenzel Glanz ; Michael Wagner ; Annika Spottke ; Karin Waegemann ; Michael Görtler ; Silke Wunderlich ; Matthias Endres ; Inga Zerr ; Gabor Petzold ; Martin Dichgans
Tatjana Wittenberg; Jan Friedrich Scheitz; Harald Prüß; Pia Sperber; Alexander Heinrich Nave; Anna Kufner Ibaroule; Julius Nicolai Meißner; Taraneh Ebrahimi; Julia Nordsiek; Niklas Michael Beckonert; Matthias Schmitz; Stefan Goebel; Timothy Bunck; Julia Schütte-Schmidt; Sabine Nuhn; Corinna Volpers; Peter Dechent; Matthias Bähr; Anna Maria Kopczak; Frank Arne Wollenweber; Christiane Huber; Holger Poppert; Tony Stöcker; Katja Neumann; Oliver Speck
von Jiayu Cao ; Stefan Roth ; Sijia Zhang ; Anna Maria Kopczak ; Samira Mami ; Yaw Asare ; Marios K. Georgakis ; Denise Messerer ; Amit Horn ; Ruth Shemer ; Charlene Jacqmarcq ; Audrey Picot ; Jack P. Green ; Christina Schlegl ; Xinghai Li ; Lukas Tomas ; Alexander Dutsch ; Thomas Liman ; Matthias Endres ; Saskia R. Wernsdorf ; Christina Fürle ; Olga Carofiglio ; Jie Zhu ; David Brough ; Martin Dichgans ; Gabor Petzold ; Annika Spottke ; Silke Wunderlich ; Inga Zerr ; Veit Hornung ; Denis Vivien ; Christian Schulz ; Yuval Dor ; Steffen Tiedt ; Hendrik Sager ; Gerrit Maximilian Große ; Arthur Liesz
The risk of early recurrent events after stroke remains high despite currently established secondary prevention strategies1. Risk is particularly high in patients with atherosclerosis, with more than 10% of patients experiencing early recurrent events1,2. 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.
Nature London [u.a.] : Nature Publ. Group, 1869 633(2024), 8029, Seite 433-441 Online-Ressource
von Friederike A. Arlt ; Pia S. Sperber ; Regina von Rennenberg ; Pimrapat Gebert ; Bianca Teegen ; Marios K. Georgakis ; Rong Fang ; Anna Dewenter ; Michael Görtler ; Gabor Petzold ; Silke Wunderlich ; Inga Zerr ; Martin Dichgans ; Harald Prüß ; Matthias Endres
Thomas Liman; Christian H Nolte; Lucia Kerti; Tatjana Wittenberg; Jan Friedrich Scheitz; Alexander Heinrich Nave; Anna Kufner; Felix J Bode; Sebastian Stösser; Julius Nicolai Meißner; Taraneh Ebrahimi; Julia Nordsiek; Niklas Michael Beckonert; Peter Hermann; Matthias Schmitz; Stefan Goebel; Julia Schütte-Schmidt; Sabine Nuhn; Corinna Volpers; Peter Dechent; Matthias Bähr; Wenzel Glanz; Steffen Tiedt; Karin Waegemann; Daniel Janowitz; Benno Ikenberg; Kathleen Bermkopf; Christiane Huber; Michael Wagner; Katja Neumann; Annika Spottke; Tony Stöcker; Marco Dühring; Oliver Speck; Emrah Düzel; Peter Bartenstein
