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No effective and specific drugs capable of reversing immunosuppression are clinically available. Evidences implicate the involvement of the vitamin D receptor (NR1I1) in sepsis\u2010induced immunosuppression. The anti\u2010malarial artesunate was investigated to determine action on sepsis\u2010induced immunosuppression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>\n                      The effect of artesunate on sepsis\u2010induced 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.\n                      <jats:italic>Vdr<\/jats:italic>\n                      ,\n                      <jats:italic>Atg16l1<\/jats:italic>\n                      and\n                      <jats:italic>NF\u2010\u03baB p65<\/jats:italic>\n                      were modified to investigate artesunate 's effect on pro\u2010inflammatory cytokines release, bacterial clearance and autophagy activities in sepsis\u2010induced immunosuppression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      Artesunate significantly reduced the mortality of caecal ligation and puncture (CLP)\u2010induced sepsis immunosuppression mice challenged with\n                      <jats:styled-content style=\"fixed-case\">\n                        <jats:italic>Pseudomonas aeruginosa<\/jats:italic>\n                      <\/jats:styled-content>\n                      and enhanced pro\u2010inflammatory cytokine release and bacterial clearance to reverse sepsis\u2010induced immunosuppression\n                      <jats:italic>in vivo<\/jats:italic>\n                      and\n                      <jats:italic>in vitro.<\/jats:italic>\n                      Mechanistically, artesunate interacted with vitamin D receptor, inhibiting its nuclear translocation, which influenced\n                      <jats:italic>ATG16L1<\/jats:italic>\n                      transcription and subsequent autophagy activity. Artesunate inhibited the physical interaction between vitamin D receptor and\n                      <jats:italic>NF\u2010\u03baB p65<\/jats:italic>\n                      in LPS\u2010tolerant macrophages and then promoted the nuclear translocation of\n                      <jats:italic>NF\u2010\u03baB p65<\/jats:italic>\n                      , which activated the transcription of\n                      <jats:italic>NF\u2010\u03baB p65<\/jats:italic>\n                      target genes such as pro\u2010inflammatory cytokines.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and Implications<\/jats:title>\n                    <jats:p>Our findings provide evidence that artesunate interacted with vitamin D receptor to reverse sepsis\u2010induced immunosuppression in an autophagy and NF\u2010\u03baB\u2010dependent manner, highlighting a novel approach for sepsis treatment and drug repurposing of artesunate has a bidirectional immunomodulator.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.15158","type":"journal-article","created":{"date-parts":[[2020,6,10]],"date-time":"2020-06-10T10:57:23Z","timestamp":1591786643000},"page":"4147-4165","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Artesunate interacts with the vitamin D receptor to reverse sepsis\u2010induced immunosuppression in a mouse model via enhancing autophagy"],"prefix":"10.1111","volume":"177","author":[{"given":"Shenglan","family":"Shang","sequence":"first","affiliation":[{"name":"Medical Research Center Southwest Hospital, Third Military Medical University (Army Medical University)  Chongqing China"},{"name":"Department of Pharmacy Southwest Hospital, Third Military Medical University (Army Medical University)  Chongqing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiaqi","family":"Wu","sequence":"additional","affiliation":[{"name":"Medical Research Center Southwest Hospital, Third Military Medical University (Army Medical University)  Chongqing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoli","family":"Li","sequence":"additional","affiliation":[{"name":"Medical Research Center Southwest Hospital, Third Military Medical University (Army Medical University)  Chongqing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Liu","sequence":"additional","affiliation":[{"name":"Medical Research Center Southwest Hospital, Third Military Medical University (Army Medical University)  Chongqing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pan","family":"Li","sequence":"additional","affiliation":[{"name":"Medical Research Center Southwest Hospital, Third Military Medical University (Army Medical University)  Chongqing China"},{"name":"Chongqing municipal Enterprise Technology Center Chongqing Shenghuaxi Pharmaceutical Co., Ltd.  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