scATAC sequencing data of subdural, dural CAMs and MG 8 weeks after repopulation
Perivascular and leptomeningeal macrophages are non-parenchymal macrophages summarized as central nervous system (CNS)-associated macrophages (CAMs) that mediate immune responses at brain boundaries. Both, CAMs and juxtaneuronal microglia are derived from prenatal yolk sac (YS) precursors, long-living and maintain their populations by homeostatic self-renewal without input from the periphery. Whereas microglia have been shown to be repopulated by CNS endogenous remnants of the same lineage following depletion, the renewal biology of CAMs is still poorly understood. Here, by combining multilineage myeloid fate mapping, bulk and single-cell profiling and high resolution confocal imaging, we show that the repopulation is strikingly different between CAMs and microglia. In contrast to microglia, CAMs do not renew exclusively cell-autonomously, but transiently utilize CCR2+Ly-6C+ monocytes after niche induction in an integrin-dependent manner. Remarkably and unlike repopulated microglia, replenished monocyte-derived CAMs remain transcriptionally and functionally distinct from their YS-derived counterparts. Finally, we established a protocol that allows to selectively exchange CAMs modulating disease response without functionally affecting parenchymal microglia. These new insights into the biology of the CNS immune system offer completely new therapeutic avenues for diverse neuroinflammatory and neurodegenerative diseases. Overall design: Two male and two/one female Mrc1CreERT2 R26tdT mice per group were treated with CTL or BLZ945 for seven consecutive days. Eight weeks after the treatment, CD45int-hi CD11b+ and CD206+/- cells were isolated from the brains of these mice, CD11b+CD206+CD64+ cells were isolated from dura mater and Ly6ChiCD115+ monocytes were isolated from blood. Dural and Brain macrophages were additionally split into tdT+ and tdT- gates and sorted. Cells from the same treatment group and of the same cell type were pooled (4 samples for BLZ945 and 3 samples for CTL) and additonally, microglia and monocytes from same condition were pooled and used for the generation of in total 8 single-cell ATAC-sequencing libraries.