Aryl hydrocarbon receptor negatively regulates NLRP3 inflammasome activity by inhibiting NLRP3 transcription
Aryl hydrocarbon receptor negatively regulates NLRP3 inflammasome activity by inhibiting NLRP3 transcription
复制标题
芳基烃受体通过抑制 NLRP3 转录负向调节 NLRP3 炎症小体活性
DOI：
10.1038/ncomms5738
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发表时间：
2014-08-01
影响因子：
16.6
通讯作者：
Zhao, Wei
中科院分区：
文献类型：
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作者：
Huai, Wanwan;Zhao, Rui;Zhao, Wei
NLRP 3炎性体是一种多蛋白复合物，在宿主防御病原体中发挥着至关重要的作用。NLRP 3蛋白水平被认为是炎性小体活化的速率限制，因此必须严格控制其表达以维持免疫稳态。然而，调节NLRP 3表达的分子机制，特别是在转录水平上，仍然是未知的。在本研究中，我们发现，芳烃受体（AhR）激活抑制NLRP 3表达，caspase-1激活和随后的IL-1β分泌在腹腔巨噬细胞，而siRNA敲低AhR具有相反的效果。AhR可与NLRP 3启动子中的异生素反应元件（XRE）结合，抑制NLRP 3的转录。此外，AhR激活抑制明矾诱导的腹膜炎在体内。因此，我们通过抑制NLRP 3的转录将AhR鉴定为NLRP 3炎性体活性的负调节剂，并建议AhR作为干预具有不受控制的炎性体活化的疾病的潜在靶标。
NLRP3 inflammasome is a multi-protein complex, which plays crucial roles in host defense against pathogens. The NLRP3 protein level is considered rate limiting for the activation of the inflammasome, thus its expression must be tightly controlled to maintain immune homeostasis. However, the molecular mechanisms that modulate NLRP3 expression, especially at the transcriptional level, remain largely unknown. In the present study, we show that aryl hydrocarbon receptor (AhR) activation inhibits NLRP3 expression, caspase-1 activation and subsequent IL-1β secretion in peritoneal macrophages, whereas siRNA knockdown of AhR has opposite effects. AhR could bind to the xenobiotic response element (XRE) in the NLRP3 promoter and inhibit NLRP3 transcription. Furthermore, AhR activation suppresses Alum-induced peritonitisin vivo. Therefore, we identified AhR as a negative regulator of NLRP3 inflammasome activity by inhibiting the transcription of NLRP3 and suggested AhR as a potential target for the intervention of diseases with uncontrolled inflammasome activation.