DNA-sensing inflammasomes cause recurrent atherosclerotic stroke

Jiayu Cao, Stefan Roth (), Sijia Zhang, Anna 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 G. Liman, Matthias Endres, Saskia R. Wernsdorf, Christina Fürle, Olga Carofiglio, Jie Zhu, David Brough, Veit Hornung, Martin Dichgans, Denis Vivien, Christian Schulz, Yuval Dor, Steffen Tiedt, Hendrik B. Sager, Gerrit M. Grosse and Arthur Liesz ()
Additional contact information
Jiayu Cao: LMU University Hospital, LMU Munich
Stefan Roth: LMU University Hospital, LMU Munich
Sijia Zhang: LMU University Hospital, LMU Munich
Anna Kopczak: LMU University Hospital, LMU Munich
Samira Mami: LMU University Hospital, LMU Munich
Yaw Asare: LMU University Hospital, LMU Munich
Marios K. Georgakis: LMU University Hospital, LMU Munich
Denise Messerer: LMU University Hospital, LMU Munich
Amit Horn: Faculty of Medicine
Ruth Shemer: Faculty of Medicine
Charlene Jacqmarcq: Institute Blood and Brain @ Caen-Normandie (BB@C)
Audrey Picot: Institute Blood and Brain @ Caen-Normandie (BB@C)
Jack P. Green: University of Manchester
Christina Schlegl: LMU University Hospital, LMU Munich
Xinghai Li: Technical University of Munich
Lukas Tomas: LMU University Hospital, LMU Munich
Alexander Dutsch: Technical University of Munich
Thomas G. Liman: Charité-Universitätsmedizin Berlin
Matthias Endres: Charité-Universitätsmedizin Berlin
Saskia R. Wernsdorf: LMU University Hospital, LMU Munich
Christina Fürle: LMU University Hospital, LMU Munich
Olga Carofiglio: LMU University Hospital, LMU Munich
Jie Zhu: LMU University Hospital, LMU Munich
David Brough: University of Manchester
Veit Hornung: LMU Munich
Martin Dichgans: LMU University Hospital, LMU Munich
Denis Vivien: Institute Blood and Brain @ Caen-Normandie (BB@C)
Christian Schulz: LMU University Hospital, LMU Munich
Yuval Dor: Faculty of Medicine
Steffen Tiedt: LMU University Hospital, LMU Munich
Hendrik B. Sager: Technical University of Munich
Gerrit M. Grosse: Hannover Medical School
Arthur Liesz: LMU University Hospital, LMU Munich

Nature, 2024, vol. 633, issue 8029, 433-441

Abstract: Abstract 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.

Date: 2024
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-024-07803-4 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:633:y:2024:i:8029:d:10.1038_s41586-024-07803-4

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-024-07803-4

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().