Commensal microbiota divergently affect myeloid subsets in the mammalian central nervous system during homeostasis and disease
Open accessAbstract
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. 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. 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.
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CAMs can respond to inflammatory and chemical cues, including signals from microbiota and mechanical cues.
“Being directly exposed to peripheral stimuli, they can respond to inflammatory and chemical cues, including signals from microbiota [369] and mechanical cues [370].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [369]
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Oakley, H., Cole, S. L., Logan, S., Maus, E., Shao, P., Craft, J., Guillozet-Bongaarts, A., Ohno, M., Disterhoft, J., Van Eldik, L., et al. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.1202-06.2006 · Cited by 3,530 · see citing works
Identification of a unique TGF-β–dependent molecular and functional signature in microglia
Butovsky, O., Jedrychowski, M. P., Moore, C. S., Cialic, R., Lanser, A. J., Gabriely, G., Koeglsperger, T., Dake, B., Wu, P. M., Doykan, C. E., et al. (2014) · Nature Neuroscience · doi:10.1038/nn.3599 · Cited by 2,543 · see citing works
Van Hove, H., Martens, L., Scheyltjens, I., De Vlaminck, K., Pombo Antunes, A. R., De Prijck, S., Vandamme, N., De Schepper, S., Van Isterdael, G., Scott, C. L., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-019-0393-4 · Cited by 1,160 · cited 5× · see citing works
“While cpM Φ expressed typical CAM signature genes (Fig 1A left), CP epi cells displayed expression of genes usually attributed as typical microglial markers (Van Hove et al , 2019) (Fig 1A right).”
InfluentialLayer V cortical neurons require microglial support for survival during postnatal development
Ueno, M., Fujita, Y., Tanaka, T., Nakamura, Y., Kikuta, J., Ishii, M., & Yamashita, T. (2013) · Nature Neuroscience · doi:10.1038/nn.3358 · Cited by 781 · see citing works
Aging-induced type I interferon response at the choroid plexus negatively affects brain function
Baruch, K., Deczkowska, A., David, E., Castellano, J. M., Miller, O., Kertser, A., Berkutzki, T., Barnett-Itzhaki, Z., Bezalel, D., Wyss-Coray, T., et al. (2014) · Science · doi:10.1126/science.1252945 · Cited by 615 · see citing works
De Novo Prediction of Stem Cell Identity using Single-Cell Transcriptome Data
Grün, D., Muraro, M. J., Boisset, J.-C., Wiebrands, K., Lyubimova, A., Dharmadhikari, G., van den Born, M., van Es, J., Jansen, E., Clevers, H., et al. (2016) · Cell Stem Cell · doi:10.1016/j.stem.2016.05.010 · Cited by 586 · see citing works
Hagemeyer, N., Hanft, K.-M., Akriditou, M.-A., Unger, N., Park, E. S., Stanley, E. R., Staszewski, O., Dimou, L., & Prinz, M. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1747-1 · Cited by 558 · see citing works
Cross-Species Single-Cell Analysis Reveals Divergence of the Primate Microglia Program
Geirsdottir, L., David, E., Keren-Shaul, H., Weiner, A., Bohlen, S. C., Neuber, J., Balic, A., Giladi, A., Sheban, F., Dutertre, C.-A., et al. (2019) · Cell · doi:10.1016/j.cell.2019.11.010 · Cited by 461 · see citing works
Self-citationThe microbiota regulate neuronal function and fear extinction learning
Chu, C., Murdock, M. H., Jing, D., Won, T. H., Chung, H., Kressel, A. M., Tsaava, T., Addorisio, M. E., Putzel, G. G., Zhou, L., et al. (2019) · Nature · doi:10.1038/s41586-019-1644-y · Cited by 421 · see citing works
Macrophages at CNS interfaces: Ontogeny and function in health and disease
Kierdorf, K., Masuda, T., Jordão, M. J. C., & Prinz, M. (2019) · Nature Reviews Neuroscience · doi:10.1038/s41583-019-0201-x · Cited by 416 · cited 5× · see citing works
“Macrophages are the first responders to infections of the brain, mediating early pathogen control and initiating downstream immune reactions (Prinz et al , 2017; Kierdorf et al , 2019).”
InfluentialHawkes, C. A., & McLaurin, J. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0805453106 · Cited by 397 · see citing works
FateID infers cell fate bias in multipotent progenitors from single-cell RNA-seq data
Herman, J. S., Sagar, & Grün, D. (2018) · Nature Methods · doi:10.1038/nmeth.4662 · Cited by 363 · see citing works
Faraco, G., Sugiyama, Y., Lane, D., Garcia-Bonilla, L., Chang, H., Santisteban, M. M., Racchumi, G., Murphy, M., Van Rooijen, N., Anrather, J., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci86950 · Cited by 350 · cited 1× · see citing works
“…support of neurons and oligodendrocytes by microglia in the brain parenchyma, or vascular remodeling and drainage of toxic protein aggregates by pvM Φ (Zhou et al , 2010; Ueno et al , 2013; Hawkes et al , 2014; Faraco et al , 2016; Hagemeyer et al , 2017; Herz et al , 2017; Kierdorf et al , 2019).”
Mrdjen, D., Pavlovic, A., Hartmann, F. J., Schreiner, B., Utz, S. G., Leung, B. P., Lelios, I., Heppner, F. L., Kipnis, J., Merkler, D., et al. (2018) · Immunity · doi:10.1016/j.immuni.2018.02.014 · Cited by 220 · cited 1× · see citing works
“It is suggested that CAM subsets are implicated in scavenging cellular debris, pathogens, and molecules (Mrdjen et al , 2018; Kierdorf et al , 2019).”
A Binary Cre Transgenic Approach Dissects Microglia and CNS Border-Associated Macrophages
Kim, J.-S., Kolesnikov, M., Peled-Hajaj, S., Scheyltjens, I., Xia, Y., Trzebanski, S., Haimon, Z., Shemer, A., Lubart, A., Van Hove, H., et al. (2021) · Immunity · doi:10.1016/j.immuni.2020.11.007 · Cited by 176 · see citing works
Mezö, C., Dokalis, N., Mossad, O., Staszewski, O., Neuber, J., Yilmaz, B., Schnepf, D., de Agüero, M. G., Ganal-Vonarburg, S. C., Macpherson, A. J., et al. (2020) · Acta Neuropathologica Communications · doi:10.1186/s40478-020-00988-5 · Cited by 120 · see citing works
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Flagged first, then by citations
Research works printed but not linked: 39
- Amit I, Winter DR, Jung S (2016) The role of the local environment and epigenetics in shaping macrophage identity and their effect on tissue homeostasis. Nat Immunol 17: 18– 25 26681458
- Brioschi S, Zhou Y, Colonna M (2020) Brain parenchymal and extraparenchymal macrophages in development, homeostasis, and disease. J Immunol 204: 294– 305 31907272 PMC7034672
- Conrad ML, Ferstl R, Teich R, Brand S, Blümer N, Yildirim AÖ, Patrascan CC, Hanuszkiewicz A, Akira S, Wagner H et al (2009) Maternal TLR signaling is required for prenatal asthma protection by the nonpathogenic microbe Acinetobacter lwoffii F78. J Exp Med 206: 2869– 2877 19995952 PMC2806458
- Cui J, Shipley FB, Shannon ML, Alturkistani O, Dani N, Webb MD, Sugden AU, Andermann ML, Lehtinen MK (2020) Inflammation of the embryonic choroid plexus barrier following maternal immune activation. Dev Cell 55: 617– 628 33038331 PMC7725967
- Ding J, Adiconis X, Simmons SK, Kowalczyk MS, Hession CC, Marjanovic ND, Hughes TK, Wadsworth MH, Burks T, Nguyen LT et al (2020) Systematic comparison of single‐cell and single‐nucleus RNA‐sequencing methods. Nat Biotechnol 38: 737– 746 32341560 PMC7289686
- Erny D, Hrabě de Angelis AL, Jaitin D, Wieghofer P, Staszewski O, David E, Keren‐Shaul H, Mahlakoiv T, Jakobshagen K, Buch T et al (2015) Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci 18: 965– 977 26030851 PMC5528863
- Erny D, Prinz M (2020) How microbiota shape microglial phenotypes and epigenetics. Glia 68: 1655– 1672 32181523
- Garzetti D, Brugiroux S, Bunk B, Pukall R, McCoy KD, Macpherson AJ, Stecher B (2017) High‐quality whole‐genome sequences of the oligo‐mouse‐microbiota bacterial community. Genome Announc 5: e00758‐17 29051233 PMC5646386
- Giannoni P, Arango‐Lievano M, Neves ID, Rousset MC, Baranger K, Rivera S, Jeanneteau F, Claeysen S, Marchi N (2016) Cerebrovascular pathology during the progression of experimental Alzheimer's disease. Neurobiol Dis 88: 107– 117 26774030
- Goldmann T, Wieghofer P, Jordão MJC, Prutek F, Hagemeyer N, Frenzel K, Amann L, Staszewski O, Kierdorf K, Krueger M et al (2016) Origin, fate and dynamics of macrophages at central nervous system interfaces. Nat Immunol 17: 797– 805 27135602 PMC4968048
- Gosselin D, Link VM, Romanoski C, Fonseca G, Eichenfield D, Spann N, Stender J, Chun H, Garner H, Geissmann F et al (2014) Environment drives selection and function of enhancers controlling tissue‐specific macrophage identities. Cell 159: 1327– 1340 25480297 PMC4364385
- Hawkes CA, Jayakody N, Johnston DA, Bechmann I, Carare RO (2014) Failure of perivascular drainage of beta‐amyloid in cerebral amyloid angiopathy. Brain Pathol 24: 396– 403 24946077 PMC8029317
- Heneka MT, Golenbock DT, Latz E (2015) Innate immunity in Alzheimer's disease. Nat Immunol 16: 229– 236 25689443
- Herz J, Pardo J, Kashkar H, Schramm M, Kuzmenkina E, Bos E, Wiegmann K, Wallich R, Peters PJ, Herzig S et al (2009) Acid sphingomyelinase is a key regulator of cytotoxic granule secretion by primary T lymphocytes. Nat Immunol 10: 761– 768 19525969
- Herz J, Filiano AJ, Smith A, Yogev N, Kipnis J (2017) Myeloid cells in the central nervous system. Immunity 46: 943– 956 28636961 PMC5657250
- Hoeffel G, Ginhoux F (2018) Fetal monocytes and the origins of tissue‐resident macrophages. Cell Immunol 330: 5– 15 29475558
- Jordão MJC, Sankowski R, Brendecke SM, Sagar, Locatelli G, Tai Y‐H, Tay TL, Schramm E, Armbruster S, Hagemeyer N et al (2019) Single‐cell profiling identifies myeloid cell subsets with distinct fates during neuroinflammation. Science 363: eaat7554 30679343
- Kawai T, Akira S (2009) The roles of TLRs, RLRs and NLRs in pathogen recognition. Int Immunol 21: 317– 337 19246554 PMC2721684
- Keren‐Shaul H, Spinrad A, Weiner A, Matcovitch‐Natan O, Dvir‐Szternfeld R, Ulland TK, David E, Baruch K, Lara‐Astaiso D, Toth B et al (2017) A unique microglia type associated with restricting development of Alzheimer's disease. Cell 169: 1276– 1290 28602351
- Kharchenko PV, Silberstein L, Scadden DT (2014) Bayesian approach to single‐cell differential expression analysis. Nat Methods 11: 740– 742 24836921 PMC4112276
- Khosravi A, Yanez A, Price JG, Chow A, Merad M, Goodridge HS, Mazmanian SK (2014) Gut microbiota promote hematopoiesis to control bacterial infection. Cell Host Microbe 15: 374– 381 24629343 PMC4144825
- Krasemann S, Madore C, Cialic R, Baufeld C, Calcagno N, El Fatimy R, Beckers L, O’Loughlin E, Xu Y, Fanek Z et al (2017) The TREM2‐APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47: 566– 581 28930663 PMC5719893
- Lavin Y, Winter D, Blecher‐Gonen R, David E, Keren‐Shaul H, Merad M, Jung S, Amit I (2014) Tissue‐resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159: 1312– 1326 25480296 PMC4437213
- Mildner A, Schlevogt B, Kierdorf K, Bottcher C, Erny D, Kummer MP, Quinn M, Bruck W, Bechmann I, Heneka MT et al (2011) Distinct and non‐redundant roles of microglia and myeloid subsets in mouse models of Alzheimer's disease. J Neurosci 31: 11159– 11171 21813677 PMC6623351
- Mildner A, Schonheit J, Giladi A, David E, Lara‐Astiaso D, Lorenzo‐Vivas E, Paul F, Chappell‐Maor L, Priller J, Leutz A et al (2017) Genomic characterization of murine monocytes reveals C/EBPbeta transcription factor dependence of Ly6C(‐) cells. Immunity 46: 849– 862 28514690
- Nagai Y, Shimazu R, Ogata H, Akashi S, Sudo K, Yamasaki H, Hayashi S, Iwakura Y, Kimoto M, Miyake K (2002) Requirement for MD‐1 in cell surface expression of RP105/CD180 and B‐cell responsiveness to lipopolysaccharide. Blood 99: 1699– 1705 11861286
- Prinz M, Erny D, Hagemeyer N (2017) Ontogeny and homeostasis of CNS myeloid cells. Nat Immunol 18: 385– 392 28323268
- Sampson TR, Debelius JW, Thron T, Janssen S, Shastri GG, Ilhan ZE, Challis C, Schretter CE, Rocha S, Gradinaru V et al (2016) Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson's disease. Cell 167: 1469– 1480 27912057 PMC5718049
- Sankowski R, Böttcher C, Masuda T, Geirsdottir L, Sagar, Sindram E, Seredenina T, Muhs A, Scheiwe C, Shah MJ et al (2019) Mapping microglia states in the human brain through the integration of high‐dimensional techniques. Nat Neurosci 22: 2098– 2110 31740814
- Shipley FB, Dani N, Xu H, Deister C, Cui J, Head JP, Sadegh C, Fame RM, Shannon ML, Flores VI et al (2020) Tracking calcium dynamics and immune surveillance at the choroid plexus blood‐cerebrospinal fluid interface. Neuron 108: 623– 639 32961128 PMC7847245
- Stecher B, Chaffron S, Käppeli R, Hapfelmeier S, Freedrich S, Weber TC, Kirundi J, Suar M, McCoy KD, von Mering C et al (2010) Like will to like: abundances of closely related species can predict susceptibility to intestinal colonization by pathogenic and commensal bacteria. PLoS Pathog 6: e1000711 20062525 PMC2796170
- Stuart T, Butler A, Hoffman P, Hafemeister C, Papalexi E, Mauck 3rd WM, Hao Y, Stoeckius M, Smibert P, Satija R (2019) Comprehensive integration of single‐cell data. Cell 177: 1888– 1902 31178118 PMC6687398
- Uchimura Y, Wyss M, Brugiroux S, Limenitakis JP, Stecher B, McCoy KD, Macpherson AJ (2016) Complete genome sequences of 12 species of stable defined moderately diverse mouse microbiota 2. Genome Announc 4: e00951‐16 27634994 PMC5026434
- Utz SG, See P, Mildenberger W, Thion MS, Silvin A, Lutz M, Ingelfinger F, Rayan NA, Lelios I, Buttgereit A et al (2020) Early fate defines microglia and non‐parenchymal brain macrophage development. Cell 181: 557– 573 32259484
- Wickham H (2016) ggplot2: elegant graphics for data analysis. New York: Springer‐Verlag
- Yu G, Wang LG, Han Y, He QY (2012) clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS 16: 284– 287 22455463 PMC3339379
- Zeisel A, Munoz‐Manchado AB, Codeluppi S, Lonnerberg P, La Manno G, Jureus A, Marques S, Munguba H, He L, Betsholtz C et al (2015) Brain structure. Cell types in the mouse cortex and hippocampus revealed by single‐cell RNA‐seq. Science 347: 1138– 1142 25700174
- Zhang D, Chen G, Manwani D, Mortha A, Xu C, Faith JJ, Burk RD, Kunisaki Y, Jang J‐E, Scheiermann C et al (2015) Neutrophil ageing is regulated by the microbiome. Nature 525: 528– 532 26374999 PMC4712631
- Zhou J, Tang PC, Qin L, Gayed PM, Li W, Skokos EA, Kyriakides TR, Pober JS, Tellides G (2010) CXCR3‐dependent accumulation and activation of perivascular macrophages is necessary for homeostatic arterial remodeling to hemodynamic stresses. J Exp Med 207: 1951– 1966 20733031 PMC2931170
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- Authors
- Sankowski, R., Ahmari, J., Mezö, C., Hrabě de Angelis, A. L., Fuchs, V., Utermöhlen, O., Buch, T., Blank, T., Gomez de Agüero, M., Macpherson, A. J., & Erny, D.
- Affiliations
- University of Freiburg (DE)
- University of Cologne (DE)
- University of Zurich (CH)
- University of Bern (CH)
- Corresponding author
- Erny, Daniel
- ORCID
- Venue
- The EMBO Journal
- Published
- 2021-10-07
- Volume
- 40
- Issue
- 23
- Pages
- e108605-e108605
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC8634130
- OpenAlex
- W3201829244
- Cited by
- 32
- References
- 16
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 5 · 2023: 8 · 2022: 4 · 2021: 1
- FWCI
- 1.80
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by-nc-nd)
- Bern Open Repository and Information System (University of Bern) (submittedVersion, cc-by-nc-nd)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by-nc-nd)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Deutsche Forschungsgemeinschaft (CRC/TRR167)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Keywords
- commensal microbiota, choroid plexus macrophages, perivascular macrophages, meningeal macrophages, microglia, germ-free mice, viral infection, Alzheimer's disease, 5xFAD mice, amyloid-beta uptake, neuroinflammation
- MeSH terms
- Alzheimer Disease, Animals, Bacteria, Central Nervous System, Female, Homeostasis, Macrophages, Male, Mice, Inbred C57BL, Myeloid Cells, Mice, Transcriptome, Microbiota
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