TY - JOUR
T1 - Commensal microbiota divergently affect myeloid subsets in the mammalian central nervous system during homeostasis and disease
AU - Sankowski, Roman
AU - Ahmari, Jasmin
AU - Mezö, Charlotte
AU - Hrabě de Angelis, Anna Lena
AU - Fuchs, Vidmante
AU - Utermöhlen, Olaf
AU - Buch, Thorsten
AU - Blank, Thomas
AU - Gomez de Agüero, Mercedes
AU - Macpherson, Andrew J.
AU - Erny, Daniel
N1 - Publisher Copyright:
© 2021 The Authors. Published under the terms of the CC BY NC ND 4.0 license
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
KW - Alzheimer’s disease
KW - CNS-associated macrophages
KW - LCMV
KW - microbiota
KW - microglia
UR - http://www.scopus.com/inward/record.url?scp=85116587413&partnerID=8YFLogxK
U2 - 10.15252/embj.2021108605
DO - 10.15252/embj.2021108605
M3 - Article
C2 - 34622466
AN - SCOPUS:85116587413
SN - 0261-4189
VL - 40
JO - EMBO Journal
JF - EMBO Journal
IS - 23
M1 - e108605
ER -