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TREM2-dependent microglial function is essential for remyelination and subsequent neuroprotection
Yuanyuan Wang1, Roxanne V Kyauk1, Yun-An A Shen1
1Department of Neuroscience, Genentech Inc., South San Francisco, California, USA.
Abstract:
Disability in multiple sclerosis (MS) is driven in part by the failure of remyelination and progressive neurodegeneration. Microglia, and specifically triggering receptor expressed on myeloid cells 2 (TREM2), a factor highly expressed in microglia, have been shown to play an important role in remyelination. Here, using a focal demyelination model in the brain, we demonstrate that demyelination is persistent in TREM2 knockout mice, lasting more than 6 weeks after lysolecithin injection and resulting in substantial neurodegeneration. We also find that TREM2 knockout mice exhibit an altered glial response following demyelination. TREM2 knockout microglia demonstrate defects in migration and phagocytosis of myelin debris. In addition, human monocyte-derived macrophages from subjects with a TREM2 mutation prevalent in human disease also show a defect in myelin debris phagocytosis. Together, we highlight the central role of TREM2 signaling in remyelination and neuroprotection. These findings provide insights into how chronic demyelination might lead to axonal damage and could help identify novel neuroprotective therapeutic targets for MS.
Insights
Triggering receptor expressed on myeloid cells 2 (TREM2) is crucial for myelin repair in the brain. Loss of TREM2 impairs microglial function, hindering remyelination and promoting neurodegeneration in multiple sclerosis models.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Multiple sclerosis (MS) disability stems from failed remyelination and neurodegeneration.
- Microglia and triggering receptor expressed on myeloid cells 2 (TREM2) are implicated in remyelination processes.
Purpose of the Study:
- To investigate the role of TREM2 in remyelination and neuroprotection within a focal demyelination model.
- To examine the impact of TREM2 deficiency on microglial function and glial response post-demyelination.
Main Methods:
- Utilized a focal brain demyelination model induced by lysolecithin injection in TREM2 knockout mice.
- Assessed persistent demyelination, neurodegeneration, and glial responses, including microglial migration and phagocytosis of myelin debris.
- Analyzed myelin debris phagocytosis in human monocyte-derived macrophages with a TREM2 mutation.
Main Results:
- TREM2 knockout mice showed persistent demyelination for over 6 weeks and significant neurodegeneration.
- TREM2 knockout microglia exhibited impaired migration and reduced phagocytosis of myelin debris.
- Human macrophages with a TREM2 mutation also displayed defective myelin debris phagocytosis.
Conclusions:
- TREM2 signaling plays a central role in effective remyelination and neuroprotection.
- Defects in TREM2 function contribute to chronic demyelination and axonal damage, relevant to MS pathogenesis.
- Targeting TREM2 signaling may offer novel therapeutic strategies for neuroprotection in MS.
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