During Treponema pallidum(T.pallidum) infection, m6A modification negatively regulates inflammatory responses in macrophages. However, whether m6A modification participates in the regulation of macrophage M2 polarization during T.pallidum infection remains unclear. Using THP-1-derived macrophages as a model, this study investigated the mechanism by which T.pallidum lipoprotein TpF1 promotes macrophage M2 polarization, and analyzed the effect of TpF1 on m6A modification in macrophages and the regulatory role of methyltransferase METTL14. Results showed that upon TpF1 stimulation, expression of M2 macrophage markers CD206 and PPARγ was significantly increased, and levels of anti-inflammatory factors TGF-β and CCL18 were upregulated at both mRNA and protein levels. In contrast, expression of M1 marker CD80 and pro-inflammatory factors IL-1β and TNF-α was significantly decreased at both mRNA and protein levels, indicating that TpF1 promotes macrophage polarization toward the M2 phenotype. Meanwhile, TpF1 upregulated global m6A levels in macrophages, accompanied by increased expression of m6A methyltransferase METTL14 and reader protein YTHDF2. Knocking down METTL14 with siRNA inhibited TpF1-induced elevation of global m6A levels and macrophage M2 polarization. Mechanistically, TpF1 promoted macrophage M2 polarization by activating the NF-κB pathway, as demonstrated by the inhibitory effect of NF-κB-specific inhibitors on M2 polarization. Further studies revealed that METTL14 knockdown significantly suppressed TpF1-induced NF-κB activation. These findings indicate that T.pallidum lipoprotein TpF1 promotes macrophage M2 polarization via METTL14-mediated regulation of the NF-κB signaling pathway, offering new insights into the immune evasion mechanisms of Treponema pallidum.
Keywords: Treponema pallidum; METTL14; TpF1; m6A modification; macrophage polarization.
© The Author(s) 2025. Published by Oxford University Press on behalf of Society for Leukocyte Biology.