The dangers posed by a stroke extend beyond the brain. A stroke can harm other organs such as the heart by triggering a systemic inflammatory response. Indeed, according to scientists based at Ludwig Maximilian University (LMU) of Munich, this inflammatory response constitutes a brain-heart axis, one that can help explain the chronic comorbidities that can develop after a stroke causes acute brain injury. These comorbidities include cognitive impairment and dementia, post-stroke depression, cardiac events, persistent vascular inflammation, and stroke-induced metabolic disturbances.
Scientists based at LMU and led by Arthur Liesz, MD, a group leader at LMU’s Institute for Stroke and Dementia Research, formed a hypothesis that the comorbidities might share a common immunological cause. But this hypothesis would be difficult to test. As the scientists were aware, the chronic effects post-stroke on systemic immunity had been underexplored.
To test the potential effect of stroke on long-term systemic inflammation, Liesz and colleagues performed a comprehensive single-cell mRNA sequencing analysis of myeloid cells from blood and multiple peripheral organs. These cells, which the scientists obtained from an experimental model of ischemic stroke, had been associated previously with inflammatory consequences of brain injury in the acute phase.
This work revealed persistent pro-inflammatory changes in monocytes/macrophages in multiple organs up to three months after brain injury, notably in the heart, leading to cardiac fibrosis and dysfunction in both mice and stroke patients. This finding was communicated recently, along with additional details, in the journal Cell, in an article titled, “Innate immune memory after brain injury drives inflammatory cardiac dysfunction.”
“IL-1β was identified as a key driver of epigenetic changes in innate immune memory,” the article’s authors wrote. “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,” the authors continued. “Such immune-targeted therapies could potentially prevent various IL-1β-mediated comorbidities, offering a framework for secondary prevention immunotherapy.”
Essentially, Liesz and colleagues found that the origin of the dysfunctions in other parts of the body lies in the immunological memory of the blood-forming cells in bone marrow. Using single-cell sequencing, the scientists demonstrated the presence of permanent proinflammatory changes in the transcriptome of certain immune cells (monocytes/macrophages) in several organs. In other words, certain gene segments are transcribed differently there after the stroke, which unbalances the proteome. These epigenetic modifications occur most frequently in the heart, where they can cause scarring and impair pumping function.
As Liesz remarked, his team “managed to identify the protein IL-1β as the main culprit for the epigenetic modifications that affect immunological memory after a stroke.”
The researchers demonstrated in a mouse model the connection between modified blood formation in bone marrow through overexpressed IL-1β and cardiac dysfunctions. Moreover, they showed that blocking IL-1b and inhibiting migration of the proinflammatory cells to the heart both successfully prevented cardiac problems after a stroke.
“These findings are hugely significant,” Liesz declared. “They open up the promise of effective therapeutic approaches for the prevention of secondary cardiac conditions after a stroke.”
The authors of the study believe that the epigenetic mechanisms they described for the reprogramming of the immune system in the brain-heart axis will create a new framework for explaining the development of—and for developing treatments for—various IL-1β-mediated comorbidities.