Wang Shaolan, Lei Ting, Zhang Kang, Zhao Wenxiang, Fang Li, Lai Baochang, Han Jie, Xiao Lei, Wang Nanping
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.
J Biol Chem. 2014 Oct 24;289(43):30075-81. doi: 10.1074/jbc.M114.578781. Epub 2014 Sep 8.
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.
孕烷X受体（PXR）是核受体超家族的成员，负责对外源生物进行解毒。我们之前的研究表明，PXR在内皮细胞（ECs）中表达，并作为解毒基因的主要调节因子，保护ECs免受外源生物的侵害。血管内皮细胞是感知病原体和外源生物的关键哨兵细胞。在本研究中，我们研究了PXR在血管先天免疫调节中的潜在功能。用PXR激动剂处理或在培养的ECs中过表达组成型活性PXR可增加关键模式识别受体的基因表达，包括Toll样受体（TLR-2、-4、-9）和NOD样受体（NOD-1和-2以及NLRP3）。特别是，PXR激动作用触发了NLRP3炎性小体的激活以及随后半胱天冬酶-1和白细胞介素-1β（IL-1β）的切割和成熟。相反，PXR的选择性拮抗或基因沉默消除了NLRP3炎性小体的激活。此外，我们通过启动子报告基因和染色质免疫沉淀分析确定NLRP3是PXR的转录靶点。总之，我们的研究结果揭示了PXR对先天免疫的一种新的调节机制，它可能作为一个主要转录因子，控制外源生物解毒和针对它们的先天免疫之间的汇聚。
