Journal
EMBO JOURNAL
Volume 40, Issue 23, Pages -Publisher
WILEY
DOI: 10.15252/embj.2021108605
Keywords
Alzheimer's disease; CNS-associated macrophages; LCMV; microbiota; microglia
Categories
Funding
- Else Kroner Fresenius Foundation
- Berta-Ottenstein-Programme for Clinician Scientists, Faculty of Medicine, University of Freiburg
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [CRC/TRR167]
- Berta-Ottenstein-Programme for Advanced Clinician Scientists, Faculty of Medicine, University of Freiburg
- Projekt DEAL
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The study reveals differential effects of microbiota on microglia and CAMs. While microbiota tightly regulate the transcriptional profiles and numbers of choroid plexus macrophages under normal conditions, acute perturbations and chronic diseases affect CAMs differently.
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.
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