Skull and vertebral bone marrow are myeloid cell reservoirs for the meninges and CNS parenchyma

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Abstract

The meninges are a membranous structure enveloping the central nervous system (CNS) that host a rich repertoire of immune cells mediating CNS immune surveillance. Here, we report that the meninges contain a pool of monocytes and neutrophils supplied not from the blood, but by adjacent skull and vertebral bone marrow. Under pathological conditions, including spinal cord injury and neuroinflammation, CNS-infiltrating myeloid cells can originate from brain borders and display transcriptional signatures distinct from their blood-derived counterparts. Thus, CNS borders are populated by myeloid cells from adjacent bone-marrow niches, strategically placed to supply innate immune cells under homeostatic and pathological conditions. These findings call for reinterpretation of immune-cell infiltration into the CNS during injury and autoimmunity and may inform future therapeutic approaches harnessing meningeal immune cells.

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Most cited references 40

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Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain.

Monica R.P. Elmore, Allison R. Najafi, Maya A. Koike … (2014)

The colony-stimulating factor 1 receptor (CSF1R) is a key regulator of myeloid lineage cells. Genetic loss of the CSF1R blocks the normal population of resident microglia in the brain that originates from the yolk sac during early development. However, the role of CSF1R signaling in microglial homeostasis in the adult brain is largely unknown. To this end, we tested the effects of selective CSF1R inhibitors on microglia in adult mice. Surprisingly, extensive treatment results in elimination of ∼99% of all microglia brain-wide, showing that microglia in the adult brain are physiologically dependent upon CSF1R signaling. Mice depleted of microglia show no behavioral or cognitive abnormalities, revealing that microglia are not necessary for these tasks. Finally, we discovered that the microglia-depleted brain completely repopulates with new microglia within 1 week of inhibitor cessation. Microglial repopulation throughout the CNS occurs through proliferation of nestin-positive cells that then differentiate into microglia. Copyright © 2014 Elsevier Inc. All rights reserved.

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Author and article information

Contributors

Andrea Cugurra: (View ORCID Profile)

Tornike Mamuladze: (View ORCID Profile)

Justin Rustenhoven: (View ORCID Profile)

Taitea Dykstra: (View ORCID Profile)

Zev J. Greenberg: (View ORCID Profile)

Zach Papadopoulos: (View ORCID Profile)

Antoine Drieu: (View ORCID Profile)

Simone Brioschi: (View ORCID Profile)

Marco Colonna: (View ORCID Profile)

Jonathan Kipnis: (View ORCID Profile)

Journal

Title: Science

Abbreviated Title: Science

Publisher: American Association for the Advancement of Science (AAAS)

ISSN (Print): 0036-8075

ISSN (Electronic): 1095-9203

Publication date (Electronic): June 03 2021

Page: eabf7844

Affiliations

[1 ]Gutenberg Research Fellowship Group of Neuroimmunology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine Main Neuroscience Network (rmn), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.

[2 ]Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA, USA.

[3 ]Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, USA.

[4 ]Department of Pediatrics, Washington University School of Medicine, Saint Louis, MO, USA.

[5 ]Neuroscience Graduate Program, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA.

Article

DOI: 10.1126/science.abf7844

PubMed ID: 34083447

SO-VID: 40d7407d-7ad5-45af-9730-816b3645153e

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