title: Aryl hydrocarbon receptor negatively regulates NLRP3 inflammasome activity by inhibiting NLRP3 transcription.
abstract: 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 peritonitis in 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.
authors.affiliation: 1] Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China [2].
authors.forename: Wanwan
authors.initials: W
authors.lastname: Huai
authors.affiliation: 1] Department of Neurosurgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, China [2].
authors.forename: Rui
authors.initials: R
authors.lastname: Zhao
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Song
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Lining
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Chengjiang
authors.initials: C
authors.lastname: Gao
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Lihui
authors.initials: L
authors.lastname: Han
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
mesh_terms: D000534:Alum Compounds; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000276:immunology; D020170:Caspase 1 / Q000235:genetics / Q000276:immunology; D004121:Dimethyl Sulfoxide; D005260:Female; D005786:Gene Expression Regulation; D058847:Inflammasomes / Q000235:genetics* / Q000276:immunology; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010538:Peritonitis / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D061251:Primary Cell Culture; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D020218:Response Elements; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D000534:Alum Compounds; D002352:Carrier Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D034741:RNA, Small Interfering; D018336:Receptors, Aryl Hydrocarbon; C041524:aluminum sulfate; D020170:Caspase 1; D004121:Dimethyl Sulfoxide