title: Xenobiotic pregnane X receptor (PXR) regulates innate immunity via activation of NLRP3 inflammasome in vascular endothelial cells.
abstract: Pregnane X receptor (PXR) is a member of nuclear receptor superfamily and responsible for the detoxification of xenobiotics. Our previously study demonstrated that PXR is expressed in endothelial cells (ECs) and acts as a master regulator of detoxification genes to protect ECs against xenobiotics. Vascular endothelial cells are key sentinel cells to sense the pathogens and xenobiotics. In this study, we examined the potential function of PXR in the regulation of innate immunity in vasculatures. Treatments with PXR agonists or overexpression of a constitutively active PXR in cultured ECs increased gene expression of the key pattern recognition receptors, including Toll-like receptors (TLR-2, -4, -9) and NOD-like receptors (NOD-1 and -2 and NLRP3). In particular, PXR agonism triggered the activation of NLRP3 inflammasome and the ensuing cleavage and maturation of caspase-1 and interleukin-1β (IL-1β). Conversely, selective antagonism or gene silencing of PXR abrogated NLRP3 inflammasome activation. In addition, we identified NLRP3 as a transcriptional target of PXR by using the promoter-reporter and ChIP assays. In summary, our findings revealed a novel regulatory mechanism of innate immune by PXR, which may act as a master transcription factor controlling the convergence between the detoxification of xenobiotics and the innate immunity against them.
authors.affiliation: From the Cardiovascular Research Center, School of Medicine, Xi'an Jiaotong University, Xi'an 710061 and.
authors.forename: Shaolan
authors.initials: S
authors.lastname: Wang
authors.affiliation: From the Cardiovascular Research Center, School of Medicine, Xi'an Jiaotong University, Xi'an 710061 and.
authors.forename: Ting
authors.initials: T
authors.lastname: Lei
authors.affiliation: From the Cardiovascular Research Center, School of Medicine, Xi'an Jiaotong University, Xi'an 710061 and.
authors.forename: Kang
authors.initials: K
authors.lastname: Zhang
authors.affiliation: From the Cardiovascular Research Center, School of Medicine, Xi'an Jiaotong University, Xi'an 710061 and.
authors.forename: Wenxiang
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Institute of Cardiovascular Science, Peking University, Beijing 100191, China.
authors.forename: Li
authors.initials: L
authors.lastname: Fang
authors.affiliation: From the Cardiovascular Research Center, School of Medicine, Xi'an Jiaotong University, Xi'an 710061 and.
authors.forename: Baochang
authors.initials: B
authors.lastname: Lai
authors.affiliation: From the Cardiovascular Research Center, School of Medicine, Xi'an Jiaotong University, Xi'an 710061 and.
authors.forename: Jie
authors.initials: J
authors.lastname: Han
authors.affiliation: From the Cardiovascular Research Center, School of Medicine, Xi'an Jiaotong University, Xi'an 710061 and.
authors.forename: Lei
authors.initials: L
authors.lastname: Xiao
authors.affiliation: From the Cardiovascular Research Center, School of Medicine, Xi'an Jiaotong University, Xi'an 710061 and Institute of Cardiovascular Science, Peking University, Beijing 100191, China nanpingwang2003@yahoo.com.
authors.forename: Nanping
authors.initials: N
authors.lastname: Wang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002417:Cattle; D042783:Endothelial Cells / Q000378:metabolism*; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D056945:Hep G2 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D058847:Inflammasomes / Q000378:metabolism*; D008969:Molecular Sequence Data; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D000077297:Pregnane X Receptor; D051192:Receptors, Pattern Recognition / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D015262:Xenobiotics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D000077297:Pregnane X Receptor; D051192:Receptors, Pattern Recognition; D011987:Receptors, Steroid; D015262:Xenobiotics
keywords: Cellular Immune Response; Endothelial Cell; Innate Immunity; Nod-like Receptor (NLR); Pattern Recognition Receptor (PRR); Toll-like Receptor (TLR); Transcription Factor; Xenobiotic