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

Abstract

This study investigates the role of the TREM2-SYK-BTK signaling pathway in microglial activation and cognitive decline. In vivo and in vitro experiments demonstrate that surgical trauma induces BTK phosphorylation in hippocampal microglia, promoting their transition towards a pro-inflammatory M1 phenotype while suppressing the anti-inflammatory M2 phenotype. In a perioperative neurocognitive disorder (PND) mouse model, hippocampal injection of AAV-BTK siRNA suppressed BTK phosphorylation, promoting microglial transition from M1 to M2 phenotype. This shift manifested as reduced pro-inflammatory cytokines (IL-1β, IL-6) and increased anti-inflammatory cytokines (IL-4, IL-10), ultimately alleviating cognitive impairment. Further mechanistic analysis revealed that TREM2 regulates microglial inflammatory balance by enhancing SYK phosphorylation to inhibit BTK activity, an effect antagonized by the SYK inhibitor R406. Subsequent studies indicate this pathway modulates neuroinflammation by regulating NF-κB signaling and NLRP3 inflammasome activation. These findings illustrate that TREM2-SYK-BTK signaling pathway is the key internal mechanism to regulate microglial polarization and neuroinflammation, which provides a new theoretical basis and potential therapeutic strategy for PND.