Innate immune memory after brain injury drives inflammatory cardiac dysfunction

TLDR

The medical burden of stroke extends beyond the brain injury itself and is largely determined by chronic comorbidities that develop secondarily. The study hypothesizes that stroke‑induced comorbidities share a common immunological cause and identifies myeloid innate immune memory as a driver of remote organ dysfunction. Single‑cell sequencing revealed persistent pro‑inflammatory changes in monocytes/macrophages in multiple organs up to 3 months after brain injury, especially in the heart, leading to cardiac fibrosis and dysfunction in mice and patients; IL‑1β was identified as a key driver of epigenetic changes, and these alterations could be transferred to naive mice, but neutralizing IL‑1β or blocking monocyte trafficking with a CCR2/5 inhibitor prevented post‑stroke cardiac dysfunction, suggesting immune‑targeted therapies could prevent IL‑1β‑mediated comorbidities.

Abstract

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.