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TREM2 regulates microglial cell activation in response to demyelination in vivo
Claudia Cantoni1, Bryan Bollman, Danilo Licastro
1Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8111, St Louis, MO, 63110, USA.
Abstract:
Microglia are phagocytic cells that survey the brain and perform neuroprotective functions in response to tissue damage, but their activating receptors are largely unknown. Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial immunoreceptor whose loss-of-function mutations in humans cause presenile dementia, while genetic variants are associated with increased risk of neurodegenerative diseases. In myeloid cells, TREM2 has been involved in the regulation of phagocytosis, cell proliferation and inflammatory responses in vitro. However, it is unknown how TREM2 contributes to microglia function in vivo. Here, we identify a critical role for TREM2 in the activation and function of microglia during cuprizone (CPZ)-induced demyelination. TREM2-deficient (TREM2(-/-)) mice had defective clearance of myelin debris and more axonal pathology, resulting in impaired clinical performances compared to wild-type (WT) mice. TREM2(-/-) microglia proliferated less in areas of demyelination and were less activated, displaying a more resting morphology and decreased expression of the activation markers MHC II and inducible nitric oxide synthase as compared to WT. Mechanistically, gene expression and ultrastructural analysis of microglia suggested a defect in myelin degradation and phagosome processing during CPZ intoxication in TREM2(-/-) microglia. These findings place TREM2 as a key regulator of microglia activation in vivo in response to tissue damage.
Insights
Triggering receptor expressed on myeloid cells 2 (TREM2) is crucial for microglia activation and function in the brain. TREM2 deficiency impairs myelin debris clearance and worsens axonal damage during demyelination.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia are brain-resident immune cells essential for neuroprotection.
- Activating receptors for microglia remain largely unidentified.
- Triggering receptor expressed on myeloid cells 2 (TREM2) is implicated in myeloid cell functions and neurodegenerative diseases.
Purpose of the Study:
- To investigate the in vivo role of TREM2 in microglia activation and function during demyelination.
- To elucidate the mechanisms by which TREM2 influences microglial responses to central nervous system (CNS) damage.
Main Methods:
- Utilized cuprizone (CPZ)-induced demyelination model in TREM2-deficient (TREM2(-/-)) and wild-type (WT) mice.
- Assessed microglial activation, proliferation, morphology, and expression of activation markers (MHC II, iNOS).
- Analyzed myelin debris clearance, axonal pathology, and clinical performance.
- Performed gene expression and ultrastructural analysis of microglia.
Main Results:
- TREM2(-/-) mice exhibited impaired myelin debris clearance and increased axonal pathology compared to WT mice.
- TREM2(-/-) microglia showed reduced proliferation and activation in demyelination areas, with resting morphology and decreased MHC II/iNOS expression.
- Microglia in TREM2(-/-) mice displayed defects in myelin degradation and phagosome processing.
Conclusions:
- TREM2 is a critical regulator of microglia activation and function in response to CNS tissue damage.
- TREM2 signaling is essential for effective myelin debris clearance and limiting axonal pathology during demyelination.
- Dysfunction of TREM2 in microglia contributes to neurodegenerative processes.
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