Innate immune memory after brain injury drives inflammatory cardiac dysfunction

Author:

Simats AORCID,Zhang S,Messerer D,Cao J,Chong F,Besson-Girard S,Carofiglio O,Filser S,Plesnila N,Braun C,Gökce Ö,Dichgans M,Hatakeyama K,Bonev B,Beltrán EORCID,Schulz C,Liesz A

Abstract

AbstractThe enormous medical burden of stroke is not only due to the brain injury itself and the acute systemic effects, but is largely determined by chronic comorbidities that develop secondarily after stroke. We hypothesized that the high rate of comorbidity developing after a stroke might have a shared immunological cause, however, the chronic effects of brain injury on systemic immunity have so far been barely investigated. Here, we identified myeloid innate immune memory as a cause of remote organ dysfunction after stroke. Using single-cell sequencing, we identified persistent pro-inflammatory transcriptomic changes in resident monocytes/macrophages in multiple organs one month after experimental ischemic brain injury, which was particularly abundant in the heart and associated with the development of cardiac fibrosis and diastolic dysfunction. A similar phenotype was seen in myocardial autopsy samples from stroke versus control patients. We observed chronic functional changes in myeloid hematopoiesis driven by post-stroke IL-1β-mediated epigenetic changes. These alterations could be transplanted to naïve recipient mice and were sufficient to induce cardiac dysfunction. By effectively blocking the trafficking of pro-inflammatory monocytes from the bone marrow to the heart using a dual CCR2/5 inhibitor, we successfully prevented post-stroke cardiac dysfunction. This approach holds promising potential as a novel immune-targeted secondary prevention therapy. We anticipate that the epigenetic immune reprogramming mechanisms detailed here for the brain-heart axis could be generalized to provide a novel framework for explaining the development of various comorbidities after acute tissue injury in remote organs.

Publisher

Cold Spring Harbor Laboratory

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