Simats, A.; Zhang, S.; Messerer, D.; Chong, F.; Beşkardeş, S.; Chivukula, A. S.; Cao, J.; Besson-Girard, S.; Montellano, F. A.; Morbach, C.; Carofiglio, O.; Ricci, A.; Roth, S.; Llovera, G.; Singh, R.; Chen, Y.; Filser, S.; Plesnila, N.; Braun, C.; Spitzer, H.; Gokce, O.; Dichgans, M.; Heuschmann, P. U.; Hatakeyama, K.; Beltrán, E.; Clauss, S.; Bonev, B.; Schulz, C.; Liesz, A.
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.