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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adoptive Transfer
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Animals
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Antigens, Differentiation / genetics
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Antigens, Differentiation / immunology
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Antigens, Ly / genetics
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Antigens, Ly / immunology
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Bacterial Proteins / immunology
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Bone Marrow Cells / cytology
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Bone Marrow Cells / immunology
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Brain / cytology
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Brain / immunology*
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Brain / radiation effects
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CX3C Chemokine Receptor 1 / genetics
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CX3C Chemokine Receptor 1 / immunology
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Cell Lineage / immunology*
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Cell Lineage / radiation effects
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Cell Proliferation
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DNA Methylation
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Gene Expression Regulation / immunology*
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Genes, Reporter
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Green Fluorescent Proteins / genetics
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Green Fluorescent Proteins / immunology
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Interferon Type I / genetics
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Interferon Type I / immunology
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Lectins, C-Type / genetics
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Lectins, C-Type / immunology
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Luminescent Proteins / immunology
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Macrophages / cytology
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Macrophages / immunology
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Macrophages / radiation effects
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Mice
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Mice, Transgenic
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Microglia / cytology
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Microglia / immunology*
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Microglia / radiation effects
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Monocytes / cytology
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Monocytes / immunology*
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Monocytes / radiation effects
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Monocytes / transplantation
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Phagocytosis
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Receptors, Mitogen / genetics
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Receptors, Mitogen / immunology
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Signal Transduction
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Transplantation Chimera
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Whole-Body Irradiation
Substances
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Antigens, Differentiation
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Antigens, Ly
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Bacterial Proteins
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CLEC12A protein, mouse
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CX3C Chemokine Receptor 1
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Cx3cr1 protein, mouse
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Interferon Type I
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Lectins, C-Type
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Luminescent Proteins
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Ly-6C antigen, mouse
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Receptors, Mitogen
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monocyte-macrophage differentiation antigen
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yellow fluorescent protein, Bacteria
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Green Fluorescent Proteins