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TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis
Francesca Cignarella1,2, Fabia Filipello1,3, Bryan Bollman1
1Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8111, St. Louis, MO, 63110, USA.
Abstract:
Multiple sclerosis (MS) is an inflammatory, demyelinating, and neurodegenerative disease of the central nervous system (CNS) triggered by autoimmune mechanisms. Microglia are critical for the clearance of myelin debris in areas of demyelination, a key step to allow remyelination. TREM2 is expressed by microglia and promotes microglial survival, proliferation, and phagocytic activity. Herein we demonstrate that TREM2 was highly expressed on myelin-laden phagocytes in active demyelinating lesions in the CNS of subjects with MS. In gene expression studies, macrophages from subjects with TREM2 genetic deficiency displayed a defect in phagocytic pathways. Treatment with a new TREM2 agonistic antibody promoted the clearance of myelin debris in the cuprizone model of CNS demyelination. Effects included enhancement of myelin uptake and degradation, resulting in accelerated myelin debris removal by microglia. Most importantly, antibody-dependent TREM2 activation on microglia increased density of oligodendrocyte precursors in areas of demyelination, as well as the formation of mature oligodendrocytes thus enhancing remyelination and axonal integrity. These results are relevant as they propose TREM2 on microglia as a potential new target to promote remyelination.
Insights
Activating TREM2 on microglia enhances myelin debris clearance and promotes remyelination in the central nervous system (CNS). This TREM2 (triggering receptor expressed on myeloid cells 2) pathway activation is a promising therapeutic target for multiple sclerosis (MS).
Area of Science:
- Neuroimmunology
- Cellular and Molecular Neuroscience
Background:
- Multiple sclerosis (MS) is a CNS disease involving inflammation, demyelination, and neurodegeneration.
- Microglia play a crucial role in clearing myelin debris to facilitate remyelination.
- TREM2 (triggering receptor expressed on myeloid cells 2) is vital for microglial function, including phagocytosis.
Purpose of the Study:
- To investigate the role of TREM2 in myelin debris clearance and remyelination in MS.
- To evaluate the therapeutic potential of TREM2 agonistic antibodies in promoting remyelination.
Main Methods:
- Analysis of TREM2 expression in active demyelinating lesions in MS patients.
- Gene expression studies on macrophages from TREM2-deficient individuals.
- Treatment with a TREM2 agonistic antibody in the cuprizone model of CNS demyelination.
Main Results:
- TREM2 was highly expressed on myelin-laden phagocytes in active MS lesions.
- TREM2 deficiency impaired macrophage phagocytic pathways.
- TREM2 agonistic antibody treatment accelerated myelin debris clearance by enhancing microglial uptake and degradation.
- TREM2 activation increased oligodendrocyte precursor density and mature oligodendrocyte formation, enhancing remyelination and axonal integrity.
Conclusions:
- TREM2 is upregulated in active MS lesions and is critical for efficient myelin debris removal.
- Targeting TREM2 with agonistic antibodies promotes remyelination and protects axonal integrity.
- TREM2 represents a potential therapeutic target for promoting CNS repair in multiple sclerosis.
