Artesunate interacts with Vitamin D receptor to reverse mouse model of sepsis-induced immunosuppression via enhancing autophagy

Shenglan Shang; Jiaqi Wu; Xiaoli Li; Xin Liu; Pan Li; Chunli Zheng; Yonghua Wang; Songqing Liu; Jiang Zheng; Hong Zhou

VDR belongs to a nuclear family receptor. Active VDR binds preferentially as a heterodimer with the retinoid X receptor (RXR) to hexameric repeats on vitamin D response elements (VDRE) in the promoter regions of target genes (Haussler et al., 1998; Orlov, Rochel, Moras & Klaholz, 2012) . As with other nuclear receptors, the nuclear translocation of RXR/VDR heterodimer functions to recruit additional cofactors that play an essential role in transcription (Haussler et al., 1998) . Herein, VDR was firstly predicted to be an interacted molecule candidate of AS by TCMSP, and then identified using PCR and WB. Moreover, we found that VDR was highly expressed and the nuclear translocation of VDR strikingly increased in LPS tolerance cells (mimic immunosuppression stage of sepsis) compared with . CC-BY-NC-ND 4.0 International license author/funder. It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the . https: //doi.org/10.1101 //doi.org/10. /2020 LPS cells (mimic cytokines storm stage), while AS treatment could markedly inhibit the high expression and the nuclear translocation of VDR. Furthermore, the interaction between AS and VDR was confirmed in the binding assay established in our lab. These results demonstrated that AS might interact with VDR to affect its activation, leading to a decline of VDR nuclear translocation. Thus, the effects of AS were investigated in presence and in absence of V D3 , which is the natural ligand of VDR. Our results showed AS's effect was eliminated when pro-incubated with V D3 , indicating that there is antagonism between V D3 and AS. These results strikingly suggest that AS might bind to the same receptor or even similar sites as V D3 .