| Title: |
Stroke induces early recurrent vascular events by inflammasome-dependent atherosclerotic plaque rupture |
| Authors: |
Liesz, Arthur; Cao, Jiayu; Roth, Stefan; Zhang, Sijia; Kopczak, Anna; Georgakis, Marios; Li, Xinghai; Dutsch, Alexander; Liman, Thomas; Endres, Matthias; Brough, David; Green, Jack; Wernsdorf, Saskia; Fürle, Christina; Carofiglio, Olga; Zhu, Jie; Asare, Yaw; Group, DEMDAS Study; Dichgans, Martin; Sager, Hendrik; Grosse, Gerrit |
| Publisher Information: |
Springer Science and Business Media LLC |
| Publication Year: |
2023 |
| Description: |
The risk of early recurrent events after stroke remains high despite currently established secondary prevention strategies. Risk is particularly high in patients with atherosclerosis, with more than 10% of patients experiencing early recurrent events. 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 ischemia, we show that stroke leads to activation of the AIM2 inflammasome in vulnerable atherosclerotic plaques via an increase of circulating cell-free DNA from the ischemic tissue. Enhanced plaque inflammation post-stroke results in plaque destabilization and atherothrombosis, finally leading to arterio-arterial 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. 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 ischemic events in atherosclerotic patients. The detailed mechanisms uncovered here provide so far 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. |
| Document Type: |
other/unknown material |
| Language: |
unknown |
| DOI: |
10.21203/rs.3.rs-2524458/v1 |
| Availability: |
http://dx.doi.org/10.21203/rs.3.rs-2524458/v1; https://www.researchsquare.com/article/rs-2524458/v1; https://www.researchsquare.com/article/rs-2524458/v1.html |
| Rights: |
https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.F3E5F881 |
| Database: |
BASE |