Acute TREM2 inhibition depletes MAFB-high microglia and hinders remyelination
Author(s)
Type
Journal Article
Abstract
We investigated the role of Triggering Receptor Expressed on Myeloid cells 2 (TREM2) in myelin regeneration in the brain. TREM2 is a receptor that activates microglia, which are crucial for clearing myelin debris and promoting remyelination. Previous studies in a mouse model of demyelination induced by the copper-chelating agent Cuprizone (CPZ) have shown that stimulation of TREM2 with a monoclonal antibody reduces demyelination, while deleting the Trem2 gene in mice impairs remyelination. Here, we blocked TREM2 function acutely with an antibody during both the demyelination and remyelination phases of the CPZ model and analyzed the impact of the antibody treatment on myelination and gene expression in single cells. We found that blocking TREM2 depleted a distinct population of microglia with high expression of the transcription factor MAFB during remyelination. The loss of these MAFB-high microglia was linked to impaired generation of myelinating oligodendrocytes. Importantly, we identified MAFB+ microglia in acute and acute-chronic brain lesions from individuals with multiple sclerosis (MS), but not in inactive lesions. We conclude that TREM2 is essential for maintaining a population of MAFB-high microglia that is associated with myelin repair. This finding has significant implications for understanding demyelinating diseases like MS and suggests that stimulating TREM2 could be a promising therapeutic approach for myelin repair.
Date Issued
2025-04-01
Date Acceptance
2025-02-18
Citation
Proceedings of the National Academy of Sciences of USA, 2025, 122 (13)
ISSN
0027-8424
Publisher
National Academy of Sciences
Start Page
e2426786122
Journal / Book Title
Proceedings of the National Academy of Sciences of USA
Volume
122
Issue
13
Copyright Statement
Copyright © 2025 the Author(s). Published by PNAS. This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/40131948
Subjects
TREM2
microglia
multiple sclerosis
myelin
transcription factor
Animals
Microglia
Receptors, Immunologic
MafB Transcription Factor
Mice
Remyelination
Membrane Glycoproteins
Multiple Sclerosis
Myelin Sheath
Cuprizone
Demyelinating Diseases
Humans
Disease Models, Animal
Mice, Inbred C57BL
Oligodendroglia
Brain
Male
Publication Status
Published
Coverage Spatial
United States
Article Number
e2426786122
Date Publish Online
2025-03-25