Commensal microbiota divergently affect myeloid subsets in the mammalian central nervous system during homeostasis and disease. (7th October 2021)

• Record Type: Journal Article
• 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
• Is Part Of: EMBO journal. Volume 40:Number 23(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-10-07
• Subjects: Alzheimer's disease -- CNS‐associated macrophages -- LCMV -- microbiota -- microglia; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2021108605
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: 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. 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.