Artesunate interacts with the Vitamin D receptor to reverse sepsis-induced immunosuppression in a mouse model via enhancing autophagy.
Br J Pharmacol. 2020 Jun 10. Epub 2020 Jun 10. PMID: 32520399
BACKGROUND AND PURPOSE: Immunosuppression is the predominant cause of mortality for sepsis because of failure to eradicate invading pathogens. No effective and specific drugs capable of reversing immunosuppression are available clinically. Evidences implicate the involvement of the vitamin D receptor (VDR) in sepsis-induced immunosuppression. Herein, artesunate (AS) was discovered to reverse sepsis-induced immunosuppression and the molecular mechanism was investigated.
EXPERIMENTAL APPROACH: The effect of AS on sepsis-induced immunosuppression was investigated in mice and in vitro. Bioinformatics predicted VDR as a candidate interactor for AS, which was then identified using PCR and immunoblotting. Vdr, Atg16l1, and NF-κB p65 were modified to investigate AS's effect on pro-inflammatory cytokines release, bacterial clearance, and autophagy activities in sepsis-induced immunosuppression.
KEY RESULTS: AS significantly reduced the mortality of cecal ligation and puncture (CLP) -induced sepsis immunosuppression mice challenged with Pseudomonas Aeruginosa, and enhanced proinflammatory cytokine release and bacterial clearance to reverse sepsis-induced immunosuppression in vivo and in vitro. Mechanistically, AS interacted with VDR, and then inhibiting its nuclear translocation, which influenced ATG16L1 transcription and subsequent autophagy activity. AS inhibited the physical interaction between VDR and NF-κB p65 in lipopolysaccharide tolerant macrophages, and then promoted the nuclear translocation of NF-κB p65, which activated the transcription of NF-κB p65 target genes such as pro-inflammatory cytokines.
CONCLUSION AND IMPLICATIONS: Our findings provide evidence that AS interacted with VDR to reverse sepsis-induced immunosuppression in an autophagy and NF-κB dependent manner, highlighting a novel approach for sepsis treatment and drug repurposing of AS as a bidirectional immunomodulator.