TREM2 inhibits rTp47-induced inflammasome activation and pyroptosis via targeting NLRP3

Background: Microglia surface receptors, particularly TREM2 (triggering receptor expressed on myeloid cells 2), play a crucial role as sensors for pathogen entry and can trigger robust immune responses. However, the specific role of TREM2 in regulating microglia's response to Treponema pallidum ( T. pallidum ) and its underlying functional mechanisms remain unclear. We aim to investigate the role of TREM2 in the inflammation caused by recombinant T. pallidum membrane protein Tp47 infection in microglia and to elucidate the associated mechanisms. Methods: The effect of rTp47 on TREM2 expression in HMO6 cells and its mechanism were evaluated using Flow cytometry, Western Blot, and Quantitative Real-Time PCR. The effect of TREM2 on the pyroptosis of HMO6 cells was evaluated by ELISA using generated CRISPR/Cas9-Mediated Knockout (KO) Cell Line. The interaction between TREM2 and NLRP3 on HMO6 pyroptosis was assessed by co-immunoprecipitation. The levels of soluble TREM2 (sTREM2), inflammatory cytokines, and pyroptosis were measured in the cerebrospinal fluid of 19 neurosyphilis and 13 non-neurosyphilis patients by ELISA. Results: r Tp47 promoted the expression of TREM2. The pyroptosis rate of HMO6 cells did not change with increasing rTp47 concentration, but TREM2 knockout (KO) augmented rTp47-induced NLRP3/caspase-1 inflammasome activation and increased the expression of pro-inflammatory cytokine IL-1β. Furthermore, we found TREM2 inhibits HMO6 cells pyroptosis by interacting with NLRP3. In addition, increased levels of CSF sTREM2 and IL-10 were observed in neurosyphilis patients compared to non-neurosyphilis patients, while TGF-β levels were significantly lower. Conclusion: r TP47 can inhibit the activation of NLRP3 inflammasome by up-regulating the expression of TREM2, so as to prevent the pyroptosis of HMO6 cells.