Innate immune memory after brain injury drives inflammatory cardiac dysfunction
Description
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 three months after ischemic brain injury, notably in the heart, leading to cardiac fibrosis and dysfunction. IL-1β was identified as a key driver of epigenetic changes in innate immune memory. These changes could be transplanted to naïve 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.
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Steps to reproduce
Single cell RNA sequencing, single nuclei ATAC sequencing, bulkmRNA sequencing