Innate immune memory after brain injury drives inflammatory cardiac dysfunction

Besides the local inflammatory immune response in the brain, stroke also alters systemic immunity. Within the acute and sub-acute phase, the systemic immune response to stroke has been described in detail over last decades. The long-term systemic immunological consequences after stroke are however still elusive. Therefore, a better understanding of these long-lasting chronic effects of stroke on systemic immunity and its impact on remote organ function and secondary comorbidities is needed. Here, we used single-cell RNA sequencing (scRNA-Seq) to investigate the chronic effect of stroke on the transcriptomic signatures of resident myeloid immune cells in various peripheral organs remote from the brain, including the lung, heart, liver, spleen, blood and bone marrow. We observed that monocytes in peripheral organs and in the bone marrow adopt a pro-inflammatory phenotype which persists chronically after stroke. Moreover, the pro-inflammatory profile of monocytes in the bone marrow was transmissible by BM transplantation to naïve recipients, indicating potentially epigenetically imprinted chronic innate immune memory after stroke. Indeed, by performing single-nuclei ATAC sequencing, we found that post-stroke myeloid immune memory after stroke is likely mediated by IL-1b-driven mechanisms, and that neutralization of the post-stroke increase in circulating IL-1b prevented myeloid immune memory.