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Cell. 2018 Jan 25;172(3):500-516.e16. doi: 10.1016/j.cell.2017.11.042. Epub 2017 Dec 21.

Microbiome Influences Prenatal and Adult Microglia in a Sex-Specific Manner.

Author information

1
Institut de Biologie de l'Ecole normale supérieure (IBENS), Ecole Normale Supérieure, CNRS, INSERM, PSL Research University, 75005 Paris, France.
2
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), Singapore 138648, Singapore.
3
Genomics and Immunoregulation, Life and Medical Sciences (LIMES) Institute, University of Bonn, 53115 Bonn, Germany.
4
Department of Immunology, Weizmann Institute of Science, 76100 Rehovot, Israel.
5
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), Singapore 138648, Singapore; Aix-Marseille Université, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML), 13288 Marseille, France.
6
Institut Pasteur, Unité Perception et Mémoire, CNRS, UMR 3571, F-75015 Paris, France.
7
National Cancer Centre, Singapore 169610, Singapore.
8
Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland.
9
Department of Reproductive Medicine, KK Women's and Children's Hospital, Singapore 229899, Singapore; KK Research Centre, KK Women's and Children's Hospital, 100 Bukit Timah Road, Singapore 229899, Singapore.
10
Genomics and Immunoregulation, Life and Medical Sciences (LIMES) Institute, University of Bonn, 53115 Bonn, Germany; Molecular Immunology in Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany.
11
Genomics and Immunoregulation, Life and Medical Sciences (LIMES) Institute, University of Bonn, 53115 Bonn, Germany; Platform of Single Cell Genomics and Epigenomics at the German Center for Neurodegenerative Diseases and the University of Bonn, 53175 Bonn, Germany.
12
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), Singapore 138648, Singapore; Myeloid Cell Biology, LIMES-Institute, University of Bonn, 53115 Bonn, Germany.
13
Lee Kong Chian School of Medicine and School of Biological Sciences, Nanyang Technological University, Singapore 639798, Singapore; Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm 17165, Sweden.
14
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), Singapore 138648, Singapore. Electronic address: florent_ginhoux@immunol.a-star.edu.sg.
15
Institut de Biologie de l'Ecole normale supérieure (IBENS), Ecole Normale Supérieure, CNRS, INSERM, PSL Research University, 75005 Paris, France. Electronic address: garel@biologie.ens.fr.

Abstract

Microglia are embryonically seeded macrophages that contribute to brain development, homeostasis, and pathologies. It is thus essential to decipher how microglial properties are temporally regulated by intrinsic and extrinsic factors, such as sexual identity and the microbiome. Here, we found that microglia undergo differentiation phases, discernable by transcriptomic signatures and chromatin accessibility landscapes, which can diverge in adult males and females. Remarkably, the absence of microbiome in germ-free mice had a time and sexually dimorphic impact both prenatally and postnatally: microglia were more profoundly perturbed in male embryos and female adults. Antibiotic treatment of adult mice triggered sexually biased microglial responses revealing both acute and long-term effects of microbiota depletion. Finally, human fetal microglia exhibited significant overlap with the murine transcriptomic signature. Our study shows that microglia respond to environmental challenges in a sex- and time-dependent manner from prenatal stages, with major implications for our understanding of microglial contributions to health and disease.

KEYWORDS:

CXCR4; antibiotics; embryogenesis; germ-free; microbiome; microglia; neurodevelopmental disorders; neuroinflammation; prenatal; sex

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