Competitive Repopulation of an Empty Microglial Niche Yields Functionally Distinct Subsets of Microglia-like Cells

Overview

Journal Nat Commun

Specialty Biology

Date 2018 Nov 20

PMID 30451869

Citations 102

Authors

Harald Lund

Melanie Pieber

Roham Parsa

Jinming Han

David Grommisch

Ewoud Ewing

Lara Kular

Maria Needhamsen

Alexander Espinosa

Emma Nilsson

Anna K Overby

Oleg Butovsky

Maja Jagodic

Xing-Mei Zhang

Robert A Harris

Affiliations

Soon will be listed here.

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 Cx3cr1R26 mice and monitored long-term repopulation. Here we show that the microglial niche is repopulated within weeks by a combination of local proliferation of CX3CR1F4/80Clec12a microglia and infiltration of CX3CR1F4/80Clec12a macrophages that arise directly from Ly6C monocytes. This colonization is independent of blood brain barrier breakdown, paralleled by vascular activation, and regulated by type I interferon. Ly6C 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.

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