Innate immune memory after brain injury drives inflammatory cardiac dysfunction

医学 冲程(发动机) 炎症 先天免疫系统 免疫系统 髓样 器官功能障碍 表观遗传学 免疫学 败血症 生物 生物化学 机械工程 基因 工程类
作者
Alba Simats,Shun Zhang,Denise Messerer,Jun Cao,Faye Chong,Simon Besson‐Girard,Olga Carofiglio,Severin Filser,Nikolaus Plesnila,Christian Braun,Özgün Gökçe,Martin Dichgans,Kinta Hatakeyama,Boyan Bonev,Eduardo Beltrán,Christian Schulz,Arthur Liesz
标识
DOI:10.1101/2023.10.04.560805
摘要

Abstract The 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.
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