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TREM2 regulates neuroinflammation by SYK-dependent inhibition of BTK activation to improve perioperative

Kaiyun Zhang1, Wenying Chi2, Junzuo Guo1

  • 1School of Anesthesiology, Shandong Second Medical University, Weifang 261053, China.

International Immunopharmacology
|January 27, 2026
PubMed

Insights

The TREM2-SYK-BTK pathway regulates microglial polarization and neuroinflammation. Targeting this pathway may offer a therapeutic strategy for perioperative neurocognitive disorder (PND) and cognitive decline.

Area of Science:

  • Neuroscience
  • Immunology
  • Cell Biology

Background:

  • Microglial activation plays a critical role in neuroinflammation and cognitive decline.
  • Surgical trauma can induce pro-inflammatory microglial responses, exacerbating cognitive impairment.
  • The TREM2-SYK-BTK signaling pathway's role in microglial polarization remains incompletely understood.

Purpose of the Study:

  • To investigate the role of the TREM2-SYK-BTK signaling pathway in microglial activation and cognitive decline.
  • To elucidate the mechanism by which this pathway regulates microglial polarization.
  • To explore its potential as a therapeutic target for perioperative neurocognitive disorder (PND).

Main Methods:

  • In vivo and in vitro experiments using mouse models.
  • Assessment of microglial phenotypes (M1/M2) and cytokine profiles.
  • Utilized AAV-BTK siRNA and SYK inhibitor R406 to modulate pathway activity.
  • Investigated downstream signaling pathways including NF-κB and NLRP3 inflammasome.

Main Results:

  • Surgical trauma induced BTK phosphorylation, promoting M1 microglial phenotype and cognitive impairment.
  • Suppression of BTK phosphorylation via AAV-BTK siRNA shifted microglia to M2 phenotype, reducing inflammation and improving cognition.
  • TREM2 enhances SYK phosphorylation to inhibit BTK activity, modulating neuroinflammation.
  • The pathway regulates NF-κB signaling and NLRP3 inflammasome activation.

Conclusions:

  • The TREM2-SYK-BTK signaling pathway is a key regulator of microglial polarization and neuroinflammation.
  • Modulating this pathway offers a potential therapeutic strategy for PND and related cognitive impairments.
  • This study provides a novel mechanistic understanding for targeting neuroinflammation.
Keywords:
Bruton's tyrosine kinase (BTK)MicrogliaNeuroinflammationPerioperative neurocognitive disorder (PND)Spleen tyrosine kinase (SYK)Triggering receptor expressed on myeloid cells 2 (TREM2)

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