Stroke induces disease-specific myeloid cells in the brain parenchyma and pia

Inflammation triggers secondary brain damage after stroke. The meninges and other CNS border compartments serve as invasion sites for leukocyte influx into the brain thus promoting tissue damage after stroke. However, the post-ischemic immune response of border compartments compared to brain parenchyma remains poorly characterized . Here, we deeply characterize tissue-resident leukocytes in meninges and brain parenchyma by flow cytometry, histology, and single cell transcriptomics after experimental stroke and discover that leukocytes respond differently to stroke depending on their site of residence. We thereby discover a unique phenotype of myeloid cells exclusive to the brain after stroke. These stroke-associated myeloid cells partially resemble neurodegenerative disease-associated microglia. They are mainly of resident microglial origin, partially conserved in humans and exhibit a lipid-phagocytosing phenotype. Blocking markers specific for these cells partially ameliorates stroke outcome thus providing a potential therapeutic target. The injury-response of myeloid cells in the CNS is thus compartmentalized, adjusted to the type of injury and may represent a therapeutic target. Overall design: Single-cell RNA profiling of CD45iv-CD45+ TRL sorted from the brain parenchyma, pia and dura at 24h and 72h after transient middle cerebral artery occlusion compared to healthy control animals.