This is a summary of Simats, A., Zhang, S., Messerer, D. et al. (2024). Innate immune memory after brain injury drives inflammatory cardiac dysfunction. Published in Cell. https://doi.org/10.1016/j.cell.2024.06.028
The challenge
A stroke not only causes immediate damage to the brain, but it can also have long-term health implications for other organs, such as the heart. However, unlike the acute inflammatory response within hours to a few days, the chronic effects of brain injury on systemic immunity are largely unknown. We hypothesized that the high rate of additional health conditions that develop after a stroke could have a common immunological cause, and result from long-term changes in the function of innate immune cells.
Our approach
To study epigenetic changes we used single-cell sequencing and mouse models. We validated our observations using clinical data from three representative stroke patients recruited by the Stroke Induced Cardiac FAILure (SICFAIL) study consortium that were followed up by cardiac echocardiography at three and 6 months after their stroke. In addition, we obtained myocardial autopsy samples from patients that had died 1–3 months after stroke or from age-matched control subjects that had died without cardiac or brain disorder
Our findings
We demonstrated that certain immune cells (monocytes/macrophages) in various organs undergo permanent proinflammatory changes in their transcriptome for up to three months after a stroke. Essentially, specific gene segments are transcribed differently, leading to an imbalance in the proteome. These epigenetic modifications most commonly occur in the heart, where they can result in cardiac fibrosis and impaired pumping function. Our research has pinpointed the protein IL-1b as the main contributor to these epigenetic alterations, which influences immunological memory after a stroke. We were able to demonstrate the connection between modified blood formation in bone marrow through overexpressed IL-1b and cardiac dysfunctions in a mouse model. Furthermore, we showed that blocking IL-1b, as well as inhibiting migration of the proinflammatory cells to the heart, successfully prevented cardiac problems after stroke.
The implications
Our findings suggest new avenues for treating and preventing heart problems that can occur after a stroke. The reprogramming of the immune system in the brain and the heart, as revealed by our research, could be the key to understanding and addressing health issues related to IL-1b.
Creating SyNergies
The research was led by Arthur Liesz and included SyNergy members Martin Dichgans, Nikolaus Plesnila, and Eduardo Beltrán and was supported by several SyNergy Hubs. Follow-up studies investigating the brain – bone marrow axis after stroke are already planned and will involve further SyNergy members to leverage their unique expertise in innate immunity and systems biology.
