Commensal microbiota divergently affect myeloid subsets in the mammalian central nervous system during homeostasis and disease

• Published in: The EMBO journal Vol. 40; no. 23; pp. e108605 - n/a
• Main Authors: Sankowski, Roman, Ahmari, Jasmin, Mezö, Charlotte, Hrabě de Angelis, Anna Lena, Fuchs, Vidmante, Utermöhlen, Olaf, Buch, Thorsten, Blank, Thomas, Gomez de Agüero, Mercedes, Macpherson, Andrew J, Erny, Daniel
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-12-2021; Blackwell Publishing Ltd; John Wiley and Sons Inc
• Subjects: Alzheimer Disease - genetics; Alzheimer Disease - immunology; Alzheimer Disease - microbiology; Alzheimer Disease - pathology; Alzheimer's disease; Animal models; Animals; Antibiotics; Bacteria - classification; Bacteria - growth & development; Bacteria - metabolism; Cell culture; Central nervous system; Central Nervous System - immunology; Central Nervous System - metabolism; Central Nervous System - microbiology; Central Nervous System - pathology; Choroid plexus; CNS‐associated macrophages; Composition; EMBO19; EMBO27; Female; Gene expression; Gene sequencing; Homeostasis; Immune response; Immune system; LCMV; Macrophages; Macrophages - immunology; Macrophages - metabolism; Macrophages - microbiology; Macrophages - pathology; Male; Mice; Mice, Inbred C57BL; Microbiota; Microglia; Myeloid Cells - immunology; Myeloid Cells - metabolism; Myeloid Cells - microbiology; Myeloid Cells - pathology; Nervous system; Neurodegenerative diseases; Perturbation; Transcription; Transcriptome; CNS‐associated macrophages; microbiota; LCMV; Alzheimer’s disease; microglia; CNS-associated macrophages
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.15252/embj.2021108605

The immune cells of the central nervous system (CNS) comprise parenchymal microglia and at the CNS border regions meningeal, perivascular, and choroid plexus macrophages (collectively called CNS‐associated macrophages, CAMs). While previous work has shown that microglial properties depend on environmental signals from the commensal microbiota, the effects of microbiota on CAMs are unknown. By combining several microbiota manipulation approaches, genetic mouse models, and single‐cell RNA‐sequencing, we have characterized CNS myeloid cell composition and function. Under steady‐state conditions, the transcriptional profiles and numbers of choroid plexus macrophages were found to be tightly regulated by complex microbiota. In contrast, perivascular and meningeal macrophages were affected to a lesser extent. An acute perturbation through viral infection evoked an attenuated immune response of all CAMs in germ‐free mice. We further assessed CAMs in a more chronic pathological state in 5xFAD mice, a model for Alzheimer’s disease, and found enhanced amyloid beta uptake exclusively by perivascular macrophages in germ‐free 5xFAD mice. Our results aid the understanding of distinct microbiota–CNS macrophage interactions during homeostasis and disease, which could potentially be targeted therapeutically.
Synopsis
Immune cells of the CNS comprise parenchymal microglia and meningeal, perivascular and choroid plexus macrophages at the border regions (CNS‐associated macrophages; CAMs). Here, we determined microbiota‐dependent CNS myeloid cell composition, gene expression profiles, and function.
Under steady‐state conditions, transcriptional profiles and numbers of choroid plexus macrophages were dependent on the microbiota status.
Perivascular and meningeal macrophages were affected to a lesser extent by gut bacteria.
Upon acute challenge with LCMV, CAMs showed an impaired immune response under germ‐free conditions.
Perivascular macrophages displayed enhanced amyloid beta uptake in 5xFAD mice under germ‐free conditions and after antibiotics treatment.
Graphical Abstract
Transcriptional profiles and functional properties of distinct murine CNS macrophage populations differentially depend on microbiota during homeostasis and conditions of acute viral challenge or neurodegeneration.