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                                                          4. Mechanisms underlying recurrent atherosclerotic stroke uncovered
                                                          News | 08.08.2024 | Research Spotlight

                                                          Mechanisms underlying recurrent atherosclerotic stroke uncovered

                                                          Recurrent strokes in the days and weeks after the initial event are a common problem in patients whose original cause was arteriosclerosis. An international team of researchers has uncovered the mechanisms underlying this process and proposed a new therapy involving DNase enzymes to break down cell-free DNA. If confirmed in humans, these findings could lead to improved stroke therapy

                                                          This is a summary of Cao, J., Roth, S., Zhang, S. et al. (2024). DNA-sensing inflammasomes cause recurrent atherosclerotic stroke. Published in Nature. https://doi.org/10.1038/s41586-024-07803-4


                                                          The challenge

                                                          The risk of early recurrent events after a stroke remains high, especially for patients with atherosclerosis, despite current secondary prevention strategies. The specific mechanisms that lead to increased vascular risk and recurrent stroke were not well understood, so we aimed to investigate them. Previous research, including our own, has indicated that stroke triggers a systemic inflammatory response, which may contribute to the progression of vascular inflammation and plaque build-up in patients with established atherosclerosis. Based on this, we hypothesized that stroke may promote subsequent vascular events through inflammatory mechanisms.


                                                          Our approach

                                                          One reason for lacking information on this topic may be the unavailability of suitable animal models to study recurrent ischemic events. Commonly used models for atherosclerosis are, in contrast to the situation of high-risk patients, less complex, not prone to rupture, and barely affect the cerebrovascular circulation. We therefore developed an adapted mouse model of rupture-prone

                                                          high-risk plaques of the carotid artery in combination with contralateral experimental stroke or with myocardial infarction. We also used patient cohorts for epidemiological analysis, carotid endarterectomy sample analysis, and myocardial infarction sample analysis.


                                                          Our findings

                                                          We showed that in the early phase after a stroke, an inflammatory response in the entire body occurs caused by cell-free DNA in the blood. This DNA is released actively from neutrophils, an innate immune cell type, and induces inflammation by activating the AIM2 inflammasome in certain immune cells. This leads to mass production of Interleukin-1, which particularly affects the tissue that is already inflamed – such as the vessels altered by arteriosclerosis. This, in turn, destabilizes high-risk plaques, which break down and release clots, leading to further strokes. Using this knowledge, we started a therapy on our mouse models. We administered DNases immediately after the first stroke, which reduced the rate of recurrent strokes by up to 80%. Because DNases cannot penetrate into cells, the DNA inside them remains unaffected by the treatment.


                                                          The implications

                                                          Our findings explain the high recurrence rate after incident ischaemic events in patients with atherosclerosis. Targeting DNA-mediated inflammasome activation after remote tissue injury represents a promising approach to improved stroke therapy. In fact, the success of our animal experiments has encouraged us to plan a clinical study, which has already been approved. We expect the trials to begin at several clinics in Germany in 2025.


                                                          Creating SyNergies

                                                          The research was led by our member Arthur Liesz and further included SyNergy member Martin Dichgans. The study was realized by using several SyNergy Hubs, patient cohorts recruited with the support of SyNergy, and the complementary expertise provided by SyNergy AIs.

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                                                          SyNergy wird von der Deutschen Forschungsgemeinschaft im Rahmen der deutschen Exzellenzstrategie gefördert (EXC 2145 SyNergy - ID 390857198). Die Exzellenzstrategie fördert herausragende Forschung an deutschen Universitäten. 

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