Decoding the Mechanism: Sodium Houttuyfonate's Impact on Macrophage M2 Polarization and Inflammation.

Pseudomonas aeruginosa, which is one of the most common opportunistic pathogenic bacteria, poses severe clinical risks for individuals with compromised immune systems, particularly concerning lung infections. Sodium houttuyfonate (SH), an active constituent isolated from Houttuynia cordata, exhibits limited direct antibacterial efficacy in vitro yet demonstrates notable therapeutic effects against bacterial infections in vivo. Nevertheless, the precise mechanisms underlying in vivo antibacterial pharmacological activity of SH remain unclear. Thus, here we investigate the mechanism by which SH alleviates P. aeruginosa-induced acute pulmonary infection, focusing on its influence on macrophage polarization signaling pathways. First, our findings demonstrate that SH effectively alleviated P. aeruginosa-induced acute pulmonary infection in mice, as evidenced by reduced inflammatory infiltration and alveolar damage in vivo. The results indicate that SH significantly modulated the expression of inflammatory mediators (IL-6, TNF-α, IL-1β, IL-10, TGF-β, Arg-1) and key signaling molecules (NF-κB, TLR4, STAT6, p38MAPK). In vitro, 24-hour SH treatment decreased NO production and attenuated macrophage phagocytosis, while shifting cytokine profiles from M1 to M2 phenotypes. Immunofluorescence and flow cytometry confirmed decreased CD86 (M1 marker) and increased CD206 (M2 marker) expression, indicating enhanced M2 polarization. Mechanistically, SH suppressed the TLR-4/MyD88/NF-κB pathway while activating the p38MAPK/STAT6 axis. Genetic manipulation further verified that SH regulates TLR-4 and p38MAPK, thereby controlling downstream signaling and inflammatory responses to combat infection. In conclusion, our study suggests that SH promotes macrophage M2 polarization and reduces excessive inflammation in late-stage P. aeruginosa-induced acute pulmonary infection by modulating macrophage polarization through the suppression of pro-inflammatory signaling via the TLR4/MyD88/NF-κB pathway and activation of the p38 MAPK/STAT6 pathway.