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Updated: May 20, 2025
Experimental Demyelination and Remyelination of Murine Spinal Cord by Focal Injection of Lysolecithin
Published on: March 26, 2015
Acute TREM2 inhibition depletes MAFB-high microglia and hinders remyelination
Jinchao Hou1,2, Roberta Magliozzi3,4, Yun Chen2,5
1Department of Anesthesiology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China.
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.
Insights
Triggering Receptor Expressed on Myeloid cells 2 (TREM2) is vital for brain myelin repair by maintaining specific microglia. Blocking TREM2 impairs myelin regeneration, suggesting TREM2 stimulation as a potential therapy for demyelinating diseases like multiple sclerosis.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia are key immune cells in the central nervous system, essential for clearing debris and promoting tissue repair.
- Triggering Receptor Expressed on Myeloid cells 2 (TREM2) is a microglial receptor implicated in demyelination and remyelination processes.
- Previous research indicates TREM2 modulation affects myelin regeneration, but its precise role in maintaining specific microglial populations during repair is unclear.
Purpose of the Study:
- To investigate the role of TREM2 in myelin regeneration within the brain.
- To analyze the impact of acute TREM2 blockade on microglial populations and oligodendrocyte differentiation during demyelination and remyelination.
- To identify TREM2-dependent microglial subsets involved in myelin repair and their relevance to multiple sclerosis.
Main Methods:
- Utilized the Cuprizone (CPZ) mouse model to induce demyelination and assess remyelination.
- Administered a monoclonal antibody to acutely block TREM2 function during CPZ treatment.
- Performed single-cell RNA sequencing to analyze gene expression and cellular changes in microglia and oligodendrocytes.
- Examined human brain lesions from multiple sclerosis patients to identify MAFB+ microglia.
Main Results:
- Acute TREM2 blockade during remyelination depleted a specific population of MAFB-high microglia.
- The loss of MAFB-high microglia correlated with impaired generation of myelinating oligodendrocytes.
- MAFB+ microglia were identified in active, but not inactive, multiple sclerosis brain lesions.
Conclusions:
- TREM2 is essential for maintaining MAFB-high microglia, a population crucial for effective myelin repair.
- This microglial subset plays a significant role in the generation of myelinating oligodendrocytes.
- Targeting TREM2 presents a potential therapeutic strategy for promoting myelin repair in demyelinating diseases such as multiple sclerosis.
