Dihydrotanshinone I, a main compound of Salvia miltiorrhiza, alleviates autoimmune and inflammatory diseases by directly targeting IRF3.

BACKGROUND

Interferon regulatory factor 3 (IRF3) is an essential component of the immune system to protect the host from aggression, but excessive IRF3 activation leads to the release of type I interferon, interferon-stimulated genes (ISGs) and pro-inflammatory factors, which closely linked to multiple inflammatory diseases. Therefore, suppression of aberrant activation of IRF3 can be applied to the therapy of inflammatory diseases and have promising applications.

METHODS

DNA or RNA can induce the release of type I interferon and pro-inflammatory cytokines, and cell models or multiple mice models were used to assess the anti-inflammatory potential of Dihydrotanshinone 1 (DHT), the main active component of Salvia miltiorrhiza, in vivo and in vitro. Mechanistically, IRF3 and P65 nuclear translocation, STING oligomerization and stimulator of interferon genes (STING)- or mitochondrial antiviral signaling protein (MAVS)-TANK-binding kinase 1 (TBK1)-IRF3 complex expression were detected to evaluate the mechanisms of DHT on the inhibition of type I interferon and pro-inflammatory cytokines.

RESULTS

DHT, an active ingredient isolated from Salvia miltiorrhiza, was effective in suppressing the aberrant secrection of interferon-β (IFN-β), ISGs and pro-inflammatory cytokines in THP-1 and BMDMs in WT or Trex1 mice. Mechanistically, DHT have no influence on the interaction of STING-TBK1, IRF3-TBK1 and MAVS-TBK1, but directly binds to IRF3 and affects the recruitment of STING to IRF3. Significantly, DHT has promising therapeutic effects on IRF3-mediated inflammatory diseases, including Trex1 deficiency-related systemic inflammatory response, obesity-induced insulin resistance, and NASH.

CONCLUSION

In conclusion, DHT, a novel inhibitor of the production of type I interferon and pro-inflammatory cytokines, is a potential candidate for the therapeutic of IRF3-driven autoimmune and inflammatory diseases.