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Photothrombotic Ischemia: A Minimally Invasive and Reproducible Photochemical Cortical Lesion Model for Mouse Stroke Studies
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Trem2 exacerbates ischemic brain injury through Gpnmb in a photothrombotic stroke model

Xuezhen Chen1,2,3, Kunyu Li1, Siyu Liu1,4

  • 1The Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.

Proceedings of the National Academy of Sciences of the United States of America
|April 14, 2026
PubMed

Insights

Triggering receptor expressed on myeloid cells 2 (Trem2) plays a detrimental role in ischemic stroke, worsening outcomes. Targeting the Trem2-Gpnmb pathway may mitigate neuroinflammation and improve stroke prognosis.

Area of Science:

  • Neuroscience
  • Immunology
  • Stroke Research

Background:

  • Microglia-mediated neuroinflammation influences neuronal survival in ischemic stroke.
  • Triggering receptor expressed on myeloid cells 2 (Trem2) has a complex role in stroke, with conflicting findings between animal models and human patients.
  • Elevated soluble Trem2 (sTrem2) in patients correlates with increased stroke risk and poor outcomes.

Purpose of the Study:

  • To investigate the specific role of Trem2 in ischemic stroke using a photothrombotic stroke model.
  • To elucidate the downstream mechanisms of Trem2 signaling in stroke.
  • To explore the potential of the Trem2-Gpnmb axis as a therapeutic target.

Main Methods:

  • Utilized a photothrombotic stroke model in mice with Trem2 depletion and sTrem2 administration.
  • Performed integrated mouse-human transcriptomic analyses to identify downstream effectors.
  • Administered soluble glycoprotein nonmetastatic B (sGpnmb) to assess its role.
  • Analyzed plasma sTrem2 and sGpnmb levels in stroke patients.

Main Results:

  • Trem2 depletion reduced infarct volume, suppressed inflammation, preserved neurons, and improved motor function.
  • Intracerebral sTrem2 administration worsened neuronal loss, amplified inflammation, and exacerbated neurological deficits.
  • Glycoprotein nonmetastatic B (Gpnmb) was identified as a downstream effector; sGpnmb abolished Trem2 depletion's protective effects.
  • Elevated plasma sTrem2 and sGpnmb levels in stroke patients correlated with poor prognosis.

Conclusions:

  • Trem2 plays a detrimental role in ischemic stroke, contrary to findings in other models.
  • The Trem2-Gpnmb axis is a key mediator of detrimental neuroinflammation in stroke.
  • sTrem2 and sGpnmb may serve as valuable biomarkers for stroke prognosis and represent potential therapeutic targets.
Keywords:
Trem2blood biomarkerischemic strokemiddle cerebral artery occlusion modelphotothrombotic model

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