TREM2 inhibits LPS-induced pyroptosis and inflammation by promoting mitophagy via SYK in BV2 cells.

Neuroinflammation is a critical factor in the pathogenesis of postoperative cognitive dysfunction (POCD). Maintaining microglial homeostasis is vital for regulating neuroinflammation, as microglial cell death can trigger an inflammatory response within the central nervous system. The triggering receptor expressed on myeloid cells 2 (TREM2) plays an essential role in supporting cell survival and modulating microglial-driven neuroinflammation. Our previous study indicated that TREM2 overexpression exerts protective effects against neuroinflammation and cognitive deficits in aged mice. However, the precise mechanisms by which TREM2 functions in microglia remain unclear. Consequently, this study aimed to examine the role of TREM2 in lipopolysaccharide (LPS)-induced cell death and neuroinflammation in BV2 cells. This research showed that TREM2 reduces LPS-induced nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)-mediated pyroptosis and the subsequent release of inflammatory factors through western blot analysis, flow cytometry, and enzyme-linked immunosorbent assay. Recent research has suggested that the loss of spleen tyrosine kinase (SYK), a downstream receptor kinase of TREM2 in microglia, results in exacerbated neuroinflammatory disease. This study further demonstrated that SYK activation via TREM2 treatment exerts neuroprotective effects by mitigating LPS-induced mitochondrial membrane potential damage, facilitating mitophagy, and inhibiting NLRP3-mediated pyroptosis in BV2 cells. Conversely, SYK inhibition by R406 led to microglial cell death and aggravated neuroinflammation, thereby reducing the neuroprotective effects of TREM2. Our findings indicate that TREM2 and SYK mitigate the inflammatory response in LPS-induced BV2 microglia and interfere with pyroptosis by enhancing mitophagy. These findings suggest that TREM2 and SYK may be valuable therapeutic targets for neuroinflammation.