The immunomodulatory effects of sodium new houttuyfonate on different states of macrophage against Aspergillus fumigatus infection via distinct mechanism in invasive pulmonary aspergillosis.

BACKGROUND: Invasive pulmonary aspergillosis (IPA) is usually caused by Aspergillus fumigatus infection and associated with high morbidity and mortality in immunocompromised patients. Sodium new houttuyfonate (SNH) has antifungal and immunomodulatory properties, but the therapeutic effect against IPA remains unknown. METHODS: The therapeutic effect of SNH in mice with IPA was determined by histopathological analysis and measurements of fungal loads. The toxicity of SNH to mouse alveolar macrophages (MH-S cells) and the changes in phagocytosis ability of MH-S cells to A. fumigatus were determined by cell counting kit-8 (CCK8), microscopic observation, respectively. The biological mechanism of SNH regulating the functional changes of MH-S cells was determined by transcriptomics, real-time quantitative polymerase chain reaction (RT-qPCR), western blot, molecular docking, microRNA sequencing, and miRNA_mRNA interaction analyses. RESULTS: Intraperitoneal injection of SNH had a therapeutic effect in mice with IPA, and 8 μg/mL of SNH was significantly enhanced the ability of MH-S cells to phagocytize and kill A. fumigatus conidia. Moreover, SNH increased antifungal activity of MH-S cells to A. fumigatus via the TLR2/TRAF6/IRF5 and TLR2/TRAF6/ERK axes, respectively. What's more, SNH inhibited the expression of miR-328-5p and miR-6975-3p in MH-S cells, which negatively regulated TLR2 expression and the phagocytosis and killing functions of MH-S cells. CONCLUSIONS: Taken together, these findings clarify the potential immunomodulatory mechanism of SNH for treatment of IPA, suggesting that SNH is effective against A. fumigatus infection.