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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., (© 2024. The Author(s).)

The medical burden of stroke extends beyond the brain injury itself and is largely determined by chronic comorbidities that develop secondarily. We hypothesized that these comorbidities might share a common immunological cause, yet chronic effects post-stroke on systemic immunity are underexplored. Here, we identify myeloid innate immune memory as a cause of remote organ dysfunction after stroke. Single-cell sequencing revealed persistent pro-inflammatory changes in monocytes/macrophages in multiple organs up to 3 months after brain injury, notably in the heart, leading to cardiac fibrosis and dysfunction in both mice and stroke patients. IL-1β was identified as a key driver of epigenetic changes in innate immune memory. These changes could be transplanted to naive mice, inducing cardiac dysfunction. By neutralizing post-stroke IL-1β or blocking pro-inflammatory monocyte trafficking with a CCR2/5 inhibitor, we prevented post-stroke cardiac dysfunction. Such immune-targeted therapies could potentially prevent various IL-1β-mediated comorbidities, offering a framework for secondary prevention immunotherapy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The bone marrow in the skull is important for shaping immune responses in the brain and meninges, but its molecular makeup among bones and relevance in human diseases remain unclear. Here, we show that the mouse skull has the most distinct transcriptomic profile compared with other bones in states of health and injury, characterized by a late-stage neutrophil phenotype. In humans, proteome analysis reveals that the skull marrow is the most distinct, with differentially expressed neutrophil-related pathways and a unique synaptic protein signature. 3D imaging demonstrates the structural and cellular details of human skull-meninges connections (SMCs) compared with veins. Last, using translocator protein positron emission tomography (TSPO-PET) imaging, we show that the skull bone marrow reflects inflammatory brain responses with a disease-specific spatial distribution in patients with various neurological disorders. The unique molecular profile and anatomical and functional connections of the skull show its potential as a site for diagnosing, monitoring, and treating brain diseases., Competing Interests: Declaration of interests M. Brendel received speaker honoraria from GE healthcare, Roche, and Life Molecular Imaging and is an advisor of Life Molecular Imaging. J.H. reports personal fees, research grants, and non-financial support from Merck, Bayer, Novartis, Roche, Biogen, and Celgene and non-financial support of the Guthy-Jackson Charitable Foundation—none in relation to this study. C.P. is inventor in a patent “Oral Phenylbutyrate for Treatment of Human 4-Repeat Tauopathies” (EP 23 156 122.6) filed by LMU Munich. T.K. has received speaker honoraria and/or personal fees for advisory boards from Bayer Healthcare, Teva Pharma, Merck, Novartis, Sanofi/Genzyme, Roche, and Biogen as well as grant support from Novartis and Chugai Pharma—none in relation to this study. M.K. has been on advisory boards for Biogen, medDay Pharmaceuticals, Novartis, and Sanofi; has received grant support from Sanofi and Biogen; and has received speaker fees from Abbvie, Almirall, Biogen, medDay Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi, and Teva—none in relation to this study. R.P. has received speaker honoraria, research support, and consultancy fees from Janssen, Eli Lilly, Biogen, Wilmar Schwabe, Takeda, Novo Nordisk, and Bayer Healthcare. N.K. has received speaker honoraria from Novartis and Regeneron and research grants from Regeneron—none in relationship to this study. M.I.T., H.S.B., M.N., and A.E. received speaker honoraria from Miltenyi Biotec—none in relation to this study. A.E. is co-founder of Deep Piction and 1X1 Biotech., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Neuroinflammation is an emerging focus of translational stroke research. Preclinical studies have demonstrated a critical role for brain-invading lymphocytes in post-stroke pathophysiology. Reducing cerebral lymphocyte invasion by anti-CD49d antibodies consistently improves outcome in the acute phase after experimental stroke models. However, clinical trials testing this approach failed to show efficacy in stroke patients for the chronic outcome 3 mo after stroke. Here, we identify a potential mechanistic reason for this phenomenon by detecting chronic T cell accumulation-evading the systemic therapy-in the post-ischemic brain. We observed a persistent accumulation of T cells in mice and human autopsy samples for more than 1 mo after stroke. Cerebral T cell accumulation in the post-ischemic brain was driven by increased local T cell proliferation rather than by T cell invasion. This observation urges re-evaluation of current immunotherapeutic approaches, which target circulating lymphocytes for promoting recovery after stroke., Competing Interests: Disclosures: The authors declare no competing interests exist., (© 2021 Heindl et al.)