Nuclear Factor E2-Related Factor-2 Negatively Regulates NLRP3 Inflammasome Activity by Inhibiting Reactive Oxygen Species-Induced NLRP3 Priming.
The NLRP3 inflammasome is a multiprotein complex that protects hosts against a variety of pathogens. However, the molecular mechanisms of modulating NLRP3 inflammasome activation, especially at the priming step, are still poorly understood. This study was designed to elucidate the negative regulation of nuclear factor E2-related factor-2 (Nrf2) on the activation of NLRP3 inflammasome.



We reported that Nrf2 activation inhibited NLRP3 expression, caspase-1 cleavage, and subsequent IL-1β generation. Compared with normal cells, Nrf2-deficient cells showed upregulated cleaved caspase-1, which were attributed to the increased transcription of NLRP3 caused by excess reactive oxygen species (ROS). Furthermore, priming of the NLRP3 inflammasome was sensitive to the exogenous ROS levels induced by H2O2or rotenone. Combined with adenosine triphosphate, rotenone triggered higher activity of the NLRP3 inflammasome compared with lipopolysaccharide, suggesting that ROS promoted the priming step. In addition, Nrf2-induced NQO1 was involved in the inhibition of the NLRP3 inflammasome. In an in vivo alum-induced peritonitis mouse model, Nrf2 activation suppressed typical IL-1 signaling-dependent inflammation, whereas Nrf2-/-mice exhibited a significant increase in the recruitment of immune cell and the generation of IL-1β compared with wild-type mice.



We elucidated the effects and possible mechanisms of Nrf2 activation-induced NQO1 expression on NLRP3 inflammasome inactivation and established a novel regulatory role of the Nrf2 pathway in ROS-induced NLRP3 priming.



We demonstrated Nrf2 negatively regulating NLRP3 inflammasome activity by inhibiting the priming step and suggested that Nrf2 could be a potential target for some uncontrolled inflammasome activation-associated diseases. Antioxid. Redox Signal. 26, 28-43.
Department of Physiology, State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing, China .
Xiuting
X
Liu
Department of Physiology, State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing, China .
Xin
X
Zhang
Department of Physiology, State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing, China .
Yang
Y
Ding
Department of Physiology, State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing, China .
Wei
W
Zhou
Department of Physiology, State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing, China .
Lei
L
Tao
Department of Physiology, State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing, China .
Ping
P
Lu
Department of Physiology, State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing, China .
Yajing
Y
Wang
Department of Physiology, State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing, China .
Rong
R
Hu
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002374:Catalase / Q000378:metabolism; D002460:Cell Line; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D058847:Inflammasomes / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D010538:Peritonitis / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000378:metabolism
D058847:Inflammasomes; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D002374:Catalase; D013482:Superoxide Dismutase; D016660:NAD(P)H Dehydrogenase (Quinone); D005978:Glutathione
NLRP3 inflammasome; Nrf2; ROS; priming