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TREM2 Impairs Glycolysis to Interrupt Microglial M1 Polarization and Inflammation via JAK2/STAT3 Axis

Chanyuan Liu1, Xueying Zhou2

  • 1Psychiatric Ward 1, Wuhan Wuchang Hospital, Wuhan, 430061, Hubei, China.

Cell Biochemistry and Biophysics
|September 6, 2024
PubMed

Insights

Triggering receptor expressed on myeloid cells 2 (TREM2) offers protection against cerebral ischemia/reperfusion injury (IRI) by reducing inflammation and glycolysis. TREM2 inactivates the JAK2/STAT3 pathway, promoting beneficial M2 macrophage polarization in stroke models.

Area of Science:

  • Neuroscience
  • Immunology
  • Cell Biology

Background:

  • Cerebral ischemia/reperfusion injury (IRI) is a major cause of ischemic stroke, leading to significant disability and mortality.
  • Triggering receptor expressed on myeloid cells 2 (TREM2) has emerged as a potential protective factor in cerebral ischemic stroke.
  • Understanding TREM2's mechanism is crucial for developing targeted therapies against stroke-related brain damage.

Purpose of the Study:

  • To elucidate the activity and downstream mechanism of TREM2 in mitigating cerebral IRI.
  • To investigate TREM2's role in regulating inflammatory responses, macrophage polarization, and glycolysis in a cellular model of stroke.

Main Methods:

  • Murine microglial BV2 cells were subjected to oxygen-glucose deprivation and reperfusion (OGD/R) to simulate cerebral IRI.
  • Western blotting, ELISA, RT-qPCR, and immunofluorescence were used to assess TREM2 expression, JAK2/STAT3 signaling, inflammatory cytokines, macrophage polarization, and glycolytic activity.
  • The effects of TREM2 manipulation and STAT3 activation were evaluated under OGD/R conditions.

Main Results:

  • OGD/R induced abnormal TREM2 expression and aberrant JAK2/STAT3 axis activation in BV2 cells.
  • Elevated TREM2 expression suppressed inflammation and glycolysis, inhibited the JAK2/STAT3 axis, and promoted M1-to-M2 macrophage polarization.
  • STAT3 activation exacerbated glycolysis, inflammation, and M1-like polarization in TREM2-overexpressing cells, indicating TREM2's inhibitory effect on these processes.

Conclusions:

  • TREM2 exhibits anti-inflammatory potential in cerebral IRI, likely by inactivating the glycolytic pathway through the JAK2/STAT3 axis.
  • TREM2 promotes a shift from pro-inflammatory M1 to anti-inflammatory M2 macrophages, contributing to neuroprotection.
  • Targeting TREM2 may offer a novel therapeutic strategy for managing ischemic stroke by modulating inflammatory and metabolic pathways.
Keywords:
GlycolysisJAK2/STAT3 axisM1/M2 polarizationMicrogliaOGD/RTREM2

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