Microglia control small vessel calcification via TREM2
Yvette Zarb1,2, Sucheta Sridhar1,2, Sina Nassiri3
1Department of Neurosurgery, Clinical Neurocentre, Zurich University Hospital, Zurich University, Zürich, Switzerland.
Abstract:
Microglia participate in central nervous system (CNS) development and homeostasis and are often implicated in modulating disease processes. However, less is known about the role of microglia in the biology of the neurovascular unit (NVU). In particular, data are scant on whether microglia are involved in CNS vascular pathology. In this study, we use a mouse model of primary familial brain calcification, Pdgfb , to investigate the role of microglia in calcification of the NVU. We report that microglia enclosing vessel calcifications, coined calcification-associated microglia, display a distinct activation phenotype. Pharmacological ablation of microglia with the CSF1R inhibitor PLX5622 leads to aggravated vessel calcification. Mechanistically, we show that microglia require functional TREM2 for controlling vascular calcification. Our results demonstrate that microglial activity in the setting of pathological vascular calcification is beneficial. In addition, we identify a previously unrecognized function of microglia in halting the expansion of vascular calcification.
Insights
Microglia play a crucial role in preventing the expansion of brain vascular calcification. Their activity, particularly via TREM2, is beneficial in central nervous system (CNS) disease.
Area of Science:
- Neuroscience
- Immunology
- Vascular Biology
Background:
- Microglia are key immune cells in the central nervous system (CNS), involved in development, homeostasis, and disease.
- The role of microglia in the neurovascular unit (NVU) and CNS vascular pathology remains underexplored.
Purpose of the Study:
- To investigate the function of microglia in the calcification of the neurovascular unit (NVU).
- To explore the mechanisms by which microglia regulate vascular calcification in a mouse model of primary familial brain calcification.
Main Methods:
- Utilized a mouse model of primary familial brain calcification (Pdgfb).
- Employed pharmacological ablation of microglia using the CSF1R inhibitor PLX5622.
- Investigated the role of TREM2 in microglial regulation of vascular calcification.
Main Results:
- Identified distinct activation phenotypes in microglia associated with vessel calcifications (calcification-associated microglia).
- Demonstrated that pharmacological ablation of microglia exacerbates vessel calcification.
- Showed that microglia require functional TREM2 to control vascular calcification.
Conclusions:
- Microglial activity is beneficial in pathological vascular calcification within the CNS.
- Microglia possess a previously unrecognized function in halting the expansion of vascular calcification.
- Targeting microglial function, potentially via TREM2, could be a therapeutic strategy for CNS vascular calcification.
