Soluble TREM2 triggers microglial dysfunction in neuromyelitis optica spectrum disorders

Area of Science:

• Neuroimmunology
• Neuroinflammation
• Neurodegenerative Diseases

Background:

• Microglia-driven neuroinflammation is central to acute demyelination in NMOSD.
• Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) is implicated in microglial activation in neurodegenerative conditions.
• The precise role and genetic basis of sTREM2 in NMOSD pathogenesis are not fully understood.

Purpose of the Study:

• To investigate the genetic association between sTREM2 and NMOSD risk.
• To elucidate the pathophysiological role of sTREM2 in NMOSD.
• To identify sTREM2 as a potential biomarker and therapeutic target.

Main Methods:

• Mendelian randomization analysis to assess genetic links.
• Measurement of CSF sTREM2 levels in NMOSD patients.
• Single-cell RNA sequencing of CSF myeloid cells.
• Transcriptomic and lipidomic profiling in a mouse model of NMOSD.

Main Results:

• A genetic association was found between elevated CSF sTREM2 and NMOSD risk.
• CSF sTREM2 levels were higher in NMOSD patients, correlating with neural injury and inflammation markers.
• sTREM2 was linked to microglial dysfunction, characterized by impaired lipid metabolism and enhanced glycolysis, potentially via NF-κB signaling.

Conclusions:

• Elevated CSF sTREM2 is a genetically associated risk factor for NMOSD.
• sTREM2 reflects microglial activation and dysfunction in NMOSD.
• sTREM2 represents a potential biomarker for NMOSD progression and a therapeutic target for neuroinflammation.