Artesunate interacts with the vitamin D receptor to reverse sepsis-induced immunosuppression in a mouse model via enhancing autophagy

Background and Purpose Immunosuppression is the predominant cause of mortality for sepsis because of failure to eradicate pathogens. No effective and specific drugs capable of reversing immunosuppression are clinically available. Evidences implicate the involvement of the vitamin D receptor (NR1I1) in sepsis-induced immunosuppression. The anti-malarial artesunate was investigated to determine action on sepsis-induced immunosuppression. Experimental Approach The effect of artesunate on sepsis-induced immunosuppression was investigated in mice and human and mice cell lines. Bioinformatics predicted vitamin D receptor as a candidate target for artesunate, which was then identified using PCR and immunoblotting.Vdr,Atg16l1andNF-kappa B p65were modified to investigate artesunate 's effect on pro-inflammatory cytokines release, bacterial clearance and autophagy activities in sepsis-induced immunosuppression. Key Results Artesunate significantly reduced the mortality of caecal ligation and puncture (CLP)-induced sepsis immunosuppression mice challenged withPseudomonas aeruginosaand enhanced pro-inflammatory cytokine release and bacterial clearance to reverse sepsis-induced immunosuppressionin vivoandin vitro.Mechanistically, artesunate interacted with vitamin D receptor, inhibiting its nuclear translocation, which influencedATG16L1transcription and subsequent autophagy activity. Artesunate inhibited the physical interaction between vitamin D receptor andNF-kappa B p65in LPS-tolerant macrophages and then promoted the nuclear translocation ofNF-kappa B p65, which activated the transcription ofNF-kappa B p65target genes such as pro-inflammatory cytokines. Conclusion and Implications Our findings provide evidence that artesunate interacted with vitamin D receptor to reverse sepsis-induced immunosuppression in an autophagy and NF-kappa B-dependent manner, highlighting a novel approach for sepsis treatment and drug repurposing of artesunate has a bidirectional immunomodulator.