Innate immune memory after brain injury drives inflammatory cardiac dysfunction

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....

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Veröffentlicht in:Cell 2024-08, Vol.187 (17), p.4637-4655.e26
Hauptverfasser: Simats, Alba, Zhang, Sijia, Messerer, Denise, Chong, Faye, Beşkardeş, Sude, Chivukula, Aparna Sharma, Cao, Jiayu, Besson-Girard, Simon, Montellano, Felipe A., Morbach, Caroline, Carofiglio, Olga, Ricci, Alessio, Roth, Stefan, Llovera, Gemma, Singh, Rashween, Chen, Yiming, Filser, Severin, Plesnila, Nikolaus, Braun, Christian, Spitzer, Hannah, Gokce, Ozgun, Dichgans, Martin, Heuschmann, Peter U., Hatakeyama, Kinta, Beltrán, Eduardo, Clauss, Sebastian, Bonev, Boyan, Schulz, Christian, Liesz, Arthur
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Sprache:eng
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Zusammenfassung: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. [Display omitted] •Acute brain ischemia leads to persistent innate immune memory•Innate immune memory causes chronic post-stroke cardiac dysfunction•IL-1β induces post-stroke-trained immunity through epigenetic modifications•Blocking IL-1β or monocyte recruitment prevents cardiac dysfunction Targeting IL-1β and monocyte trafficking after ischemic stroke in the brain limits subsequent cardiac pathology, suggesting a way to prevent comorbidities due to secondary organ damage.
ISSN:0092-8674
1097-4172
1097-4172
DOI:10.1016/j.cell.2024.06.028