Abstract | 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, Atg16l1 and NF-κB p65 were 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 with Pseudomonas aeruginosa and enhanced pro-inflammatory cytokine release and bacterial clearance to reverse sepsis-induced immunosuppression in vivo and in vitro. Mechanistically, artesunate interacted with vitamin D receptor, inhibiting its nuclear translocation, which influenced ATG16L1 transcription and subsequent autophagy activity. Artesunate inhibited the physical interaction between vitamin D receptor and NF-κB p65 in LPS-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:
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Authors | Shenglan Shang, Jiaqi Wu, Xiaoli Li, Xin Liu, Pan Li, Chunli Zheng, Yonghua Wang, Songqing Liu, Jiang Zheng, Hong Zhou |
Journal | British journal of pharmacology
(Br J Pharmacol)
Vol. 177
Issue 18
Pg. 4147-4165
(09 2020)
ISSN: 1476-5381 [Electronic] England |
PMID | 32520399
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2020 The British Pharmacological Society. |
Chemical References |
- NF-kappa B
- Receptors, Calcitriol
- Artesunate
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Topics |
- Animals
- Artesunate
(pharmacology)
- Autophagy
- Female
- Immunosuppression Therapy
- Male
- Mice
- Mice, Inbred BALB C
- NF-kappa B
- Receptors, Calcitriol
(drug effects)
- Sepsis
(drug therapy)
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