Dual regulation of antiviral IFN response by : Therapeutic implications for influenza.

(SR) is widely used in Chinese medicine for influenza treatment; however, the mechanisms underlying its effect remain unknown. Here, we report, for the first time, that the therapeutic effects of SR on influenza involve regulation of antiviral interferons (IFNs), type I and type III IFNs (IFN-Is and IFN-IIIs, respectively), particularly through the modulation of IFN-I production and its downstream effects in a cell type-specific manner. SR treatment resulted in symptomatic improvement in A/Puerto Rico/8/34 (H1N1) virus (PR8)-infected mice. It exhibited direct antiviral activity in the early stages of virus infection in A/WSN/33 (H1N1) (WSN)-infected Madin-Darby canine kidney (MDCK) cells. Next, we investigated the effects of SR on the upstream antiviral IFN pathways and downstream effects in human lung adenocarcinoma (A549) cells, human monocytic leukemia (THP-1) cells, and neutrophils (Neu). SR exhibited dual regulatory roles, enhancing the production and activity of antiviral IFNs via the nuclear factor-kappaB (NF-κB)/IFN regulatory factor 3 (IRF3) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathways. It also reduced IFN-I-induced neutrophil inflammation by inhibiting reactive oxygen species (ROS) and neutrophil extracellular trap (NET) production, and alleviated inflammation in A549 and THP-1 cells via NF-κB/cFOS or mitogen-activated protein kinase (MAPK)/c-Jun signaling. Subsequently, the importance of IFN-I/IFN-III was verified using IFN alpha receptor 1 ( ) and IFN lambda receptor 1 () mice. The absence of IFNAR or IFNLR significantly diminished the therapeutic effect of SR against influenza, highlighting its dependence on the IFN-I/IFN-III systems. Finally, a delayed drug administration experiment in PR8-infected mice revealed that the therapeutic effect of SR heavily relies on early induction of IFN. Overall, our findings offer valuable insights for the clinical utilization of SR, as well as for further exploration of antiviral treatments.