Competitive repopulation of an empty microglial yields functionally distinct subsets of microglia-like cells

ABSTRACT: Although most tissue macrophages are embryonically derived it is evident that circulating monocytes can compete for virtually any macrophage niche. Monocytes can thus become long-lived replacements of tissue macrophages that are indistinguishable from their embryonic counterparts, but the factors regulating this process are incompletely understood. To study niche competition in the CNS we depleted microglia with >95% efficiency using CX3CR1CreER/+R26DTA/+ mice and monitored long-term repopulation. The microglial niche was repopulated within weeks by a combination of local microglia proliferation giving rise to CX3CR1+F4/80lowClec12a– microglia, as well as infiltration of CX3CR1+F4/80hiClec12a+ macrophages. Adoptive transfer experiments demonstrated that peripherally-derived macrophages arose directly from Ly6Chi monocytes without contribution from hematopoietic progenitors and was independent of BBB breakdown. After repopulation we sorted microglia and monocyte-derived macrophages and performed transcriptional, epigenetic (DNA methylation) and ex vivo functional profiling. This revealed that Ly6Chi monocytes upregulated microglia gene expression and adopted microglia DNA methylation signatures. However, in contrast to proliferating microglia, which rapidly regained their homeostatic gene signature, monocyte-derived macrophages retained a distinct gene signature associated with antigen presentation, interferon signaling and chemotaxis. This translated into functional changes in monocyte-derived macrophages, as demonstrated by differences in surface marker expression, phagocytosis and cytokine production. Our results demonstrate that monocytes are imprinted by the CNS microenvironment but remain transcriptionally, epigenetically and functionally distinct. This may have implications for neuroinflammatory disease states and direct design of novel therapies.

ORGANISM(S): Mus musculus

PROVIDER: GSE121409 | GEO | 2018/10/19

REPOSITORIES: GEO