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.

Dihydrotanshinone I; IRF3; Insulin resistance; Nonalcoholic steatohepatitis; TREX1 deficiency; Type I interferon.