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

Harald Lund, Melanie Pieber, Roham Parsa, Jinming Han, David Grommisch, Ewoud Ewing, Lara Kular, Maria Needhamsen, Alexander Espinosa, Emma Nilsson, Anna K. Överby, Oleg Butovsky, Maja Jagodic, Xing-Mei Zhang and Robert A. Harris ()
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Harald Lund: Karolinska Hospital Solna
Melanie Pieber: Karolinska Hospital Solna
Roham Parsa: Karolinska Hospital Solna
Jinming Han: Karolinska Hospital Solna
David Grommisch: Karolinska Hospital Solna
Ewoud Ewing: Karolinska Hospital Solna
Lara Kular: Karolinska Hospital Solna
Maria Needhamsen: Karolinska Hospital Solna
Alexander Espinosa: Karolinska Hospital Solna
Emma Nilsson: Umeå University
Anna K. Överby: Umeå University
Oleg Butovsky: Harvard Medical School
Maja Jagodic: Karolinska Hospital Solna
Xing-Mei Zhang: Karolinska Hospital Solna
Robert A. Harris: Karolinska Hospital Solna

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07295-7

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