Shenglan Shang1,2, Jiaqi Wu1, Xiaoli Li1, Xin Liu1, Pan Li1,3, Chunli Zheng4, Yonghua Wang4, Songqing Liu2, Jiang Zheng1, Hong Zhou1,3,5. 1. Medical Research Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China. 2. Department of Pharmacy, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China. 3. Chongqing municipal Enterprise Technology Center, Chongqing Shenghuaxi Pharmaceutical Co., Ltd., Chongqing, China. 4. Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, China. 5. Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, Xi'an, Shanxi, China.
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: Our findings provide evidence that artesunate interacted with vitamin D receptor to reverse sepsis-induced immunosuppression in an autophagy and NF-κB-dependent manner, highlighting a novel approach for sepsis treatment and drug repurposing of artesunate has a bidirectional immunomodulator.
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 receptoras 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: Our findings provide evidence that artesunate interacted with vitamin D receptor to reverse sepsis-induced immunosuppression in an autophagy and NF-κB-dependent manner, highlighting a novel approach for sepsis treatment and drug repurposing of artesunate has a bidirectional immunomodulator.
Authors: Mervyn Singer; Clifford S Deutschman; Christopher Warren Seymour; Manu Shankar-Hari; Djillali Annane; Michael Bauer; Rinaldo Bellomo; Gordon R Bernard; Jean-Daniel Chiche; Craig M Coopersmith; Richard S Hotchkiss; Mitchell M Levy; John C Marshall; Greg S Martin; Steven M Opal; Gordon D Rubenfeld; Tom van der Poll; Jean-Louis Vincent; Derek C Angus Journal: JAMA Date: 2016-02-23 Impact factor: 56.272
Authors: Steve P H Alexander; Richard E Roberts; Brad R S Broughton; Christopher G Sobey; Christopher H George; S Clare Stanford; Giuseppe Cirino; James R Docherty; Mark A Giembycz; Daniel Hoyer; Paul A Insel; Angelo A Izzo; Yong Ji; David J MacEwan; Jonathan Mangum; Sue Wonnacott; Amrita Ahluwalia Journal: Br J Pharmacol Date: 2018-02 Impact factor: 8.739
Authors: Shaoping Wu; Yong-Guo Zhang; Rong Lu; Yinglin Xia; David Zhou; Elaine O Petrof; Erika C Claud; Di Chen; Eugene B Chang; Geert Carmeliet; Jun Sun Journal: Gut Date: 2014-07-30 Impact factor: 23.059