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

Abstract

Circulating monocytes can compete for virtually any tissue macrophage niche and become long-lived replacements that are phenotypically indistinguishable from their embryonic counterparts. As the factors regulating this process are incompletely understood, we studied niche competition in the brain by depleting microglia with >95% efficiency using Cx3cr1CreER/+R26DTA/+ mice and monitored long-term repopulation. Here we show that the microglial niche is repopulated within weeks by a combination of local proliferation of CX3CR1+F4/80lowClec12a– microglia and infiltration of CX3CR1+F4/80hiClec12a+ macrophages that arise directly from Ly6Chi monocytes. This colonization is independent of blood brain barrier breakdown, paralleled by vascular activation, and regulated by type I interferon. Ly6Chi monocytes upregulate microglia gene expression and adopt microglia DNA methylation signatures, but retain a distinct gene signature from proliferating microglia, displaying altered surface marker expression, phagocytic capacity and cytokine production. Our results demonstrate that monocytes are imprinted by the CNS microenvironment but remain transcriptionally, epigenetically and functionally distinct.

When is a control not a control? Reactive microglia occur throughout the control contralateral visual pathway in experimental glaucoma

“…We demonstrate that an early increase in monocytes, but not microglia, and a late increase in microglia, but not monocytes occurs following sustained periods of OHT. These data suggest that monocytes infiltrate the retina and become microglia-like monocyte derived macrophages, as has been reported in Alzheimer's disease and other neurodegenerative diseases and in retinal photoreceptor degeneration (96)(97)(98)(99)(100).…”

Plaque-associated myeloid cells derive from resident microglia in an Alzheimer’s disease model

“…However, recent work has refuted this assertion (Mrdjen et al, 2018). Transcriptomic studies (Keren-Shaul et al, 2017; Krasemann et al, 2017) have allowed delineation of microglia from macrophages and other immune cells, but have not been able to resolve the issue of ontogenic origin of the plaque-associated cells, owing to the rapid and diverse changes in myeloid cell gene expression in the brain microenvironment (Lund et al, 2018).…”

Protective Microglial Subset in Development, Aging, and Disease: Lessons From Transcriptomic Studies

“…More recently, studies have characterized repopulating microglia, to assess whether and how they differ from the original microglia and whether these differences could account for the positive outcomes of microglial depletion strategies. Although morphological differences have been reported (101), most studies focused on gene expression analysis (98,(101)(102)(103)(104). Two of the early studies advocated for repopulating microglia being functionally similar to resident control microglia (98,101).…”

“…Two of the early studies advocated for repopulating microglia being functionally similar to resident control microglia (98,101). However, closer examination and more recent studies, including single-cell RNA-seq, suggest that these cells differ transcriptionally (98,(102)(103)(104). Interestingly, Zhan et al compared the repopulating microglial signature to the neonatal microglial signature (104), putting forward the idea that newly formed microglia resemble developmental microglia, before adopting a more mature phenotype.…”