Microglia depletion exacerbates demyelination and impairs remyelination in a neurotropic coronavirus infection

Alan Sariol, Samantha Mackin, Merri Grace Allred, Chen Ma, Yu Zhou, Qinran Zhang, Xiufen Zou, Juan E. Abrahante, David K. Meyerholz, Stanley Perlman

Research output: Contribution to journalArticlepeer-review

Abstract

Microglia are considered both pathogenic and protective during recovery from demyelination, but their precise role remains ill defined. Here, using an inhibitor of colony stimulating factor 1 receptor (CSF1R), PLX5622, and mice infected with a neurotropic coronavirus (mouse hepatitis virus [MHV], strain JHMV), we show that depletion of microglia during the time of JHMV clearance resulted in impaired myelin repair and prolonged clinical disease without affecting the kinetics of virus clearance. Microglia were required only during the early stages of remyelination. Notably, large deposits of extracellular vesiculated myelin and cellular debris were detected in the spinal cords of PLX5622-treated and not control mice, which correlated with decreased numbers of oligodendrocytes in demyelinating lesions in drug-treated mice. Furthermore, gene expression analyses demonstrated differential expression of genes involved in myelin debris clearance, lipid and cholesterol recycling, and promotion of oligodendrocyte function. The results also demonstrate that microglial functions affected by depletion could not be compensated by infiltrating macrophages. Together, these results demonstrate that microglia play key roles in debris clearance and in the initiation of remyelination following infection with a neurotropic coronavirus but are not necessary during later stages of remyelination.

Original languageEnglish (US)
Pages (from-to)24464-24474
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number39
DOIs
StatePublished - Sep 29 2020

Bibliographical note

Funding Information:
We thank Dr. Jian Zheng and Sunnie Hsiung for a critical review of the paper. Supported, in part, by Grants from the NIH (RO1 NS36592 [S.P.] and 2T32 GM067795 [A.S.]) and National Multiple Sclerosis Society (RG 5340-A-7). The authors acknowledge use of the University of Iowa Central Microscopy Research Facility and Flow Cytometry Facility, a core resource supported by the Vice President for Research & Economic Development and the Holden Comprehensive Cancer Center and the Carver College of Medicine.

Funding Information:
ACKNOWLEDGMENTS. We thank Dr. Jian Zheng and Sunnie Hsiung for a critical review of the paper. Supported, in part, by Grants from the NIH (RO1 NS36592 [S.P.] and 2T32 GM067795 [A.S.]) and National Multiple Sclerosis Society (RG 5340-A-7). The authors acknowledge use of the University of Iowa Central Microscopy Research Facility and Flow Cytometry Facility, a core resource supported by the Vice President for Research & Economic Development and the Holden Comprehensive Cancer Center and the Carver College of Medicine.

Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.

Keywords

  • Coronavirus
  • Microglia
  • Neuroinflammation
  • Remyelination
  • Virus-induced demyelination

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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