title: Nuclear factor E2-related factor-2 (Nrf2) is required for NLRP3 and AIM2 inflammasome activation.
abstract: Despite the number of extensive studies on the immune function and signaling of inflammasomes in various diseases, the activating mechanism of inflammasome, especially the NLRP3 inflammasome, is not fully understood. Nuclear factor E2-related Factor-2 (Nrf2), a key transcription factor that regulates cellular redox homeostasis, has been reported to play both protective and pathogenic roles depending on the disease conditions through undefined mechanism. This study reveals an essential role of Nrf2 in inflammasome activation. LPS stimulation increased Nrf2 protein levels in a Myd88-dependent manner. When compared with wild-type controls, Nrf2-deficient (Nrf2(-/-)) macrophages showed decreased maturation and secretion of caspase-1 and IL-1β and reduced apoptosis-associated speck-like protein containing CARD (ASC) speck formation in response to various NLRP3 and AIM2 inflammasome stimuli. In contrast, NLRC4 inflammasome activation was not controlled by Nrf2. Biochemical analysis revealed that Nrf2 appeared in the ASC-enriched cytosolic compartment after NLRP3 inflammasome activation. Furthermore, mitochondrial reactive oxygen species-induced NLRP3 activation also required Nrf2. Nrf2(-/-) mice showed a dramatic decrease in immune cell recruitment and IL-1β generation in alum-induced peritonitis, which is a typical IL-1 signaling-dependent inflammation animal model. This work discovered a critical proinflammatory effect of Nrf2 by mediating inflammasome activation.
authors.affiliation: From the Lineberger Comprehensive Cancer Center, Department of Surgery, University of North Carolina, Chapel Hill, North Carolina 27599.
authors.forename: Changcheng
authors.initials: C
authors.lastname: Zhao
authors.affiliation: From the Lineberger Comprehensive Cancer Center, Department of Surgery, University of North Carolina, Chapel Hill, North Carolina 27599.
authors.forename: Devyn D
authors.initials: DD
authors.lastname: Gillette
authors.affiliation: From the Lineberger Comprehensive Cancer Center, Department of Surgery, University of North Carolina, Chapel Hill, North Carolina 27599.
authors.forename: Xinghui
authors.initials: X
authors.lastname: Li
authors.affiliation: From the Lineberger Comprehensive Cancer Center, Department of Surgery, University of North Carolina, Chapel Hill, North Carolina 27599.
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: From the Lineberger Comprehensive Cancer Center, Department of Surgery, University of North Carolina, Chapel Hill, North Carolina 27599 haiwen@med.unc.edu.
authors.forename: Haitao
authors.initials: H
authors.lastname: Wen
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C540422:Aim2 protein, mouse; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; C512299:Ipaf protein, mouse; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D051267:NF-E2-Related Factor 2; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C495636:Nfe2l2 protein, mouse; C492716:Nlrp3 protein, mouse; D009687:Nuclear Proteins; D020170:Caspase 1