title: Opposing effects of Nrf2 and Nrf2-activating compounds on the NLRP3 inflammasome independent of Nrf2-mediated gene expression.
abstract: The transcription factor Nrf2 regulates the expression of genes required for protection from xenobiotic and oxidative stress. Under normal conditions Nrf2 is constantly degraded upon ubiquitination, mediated by the Nrf2 inhibitor Keap1. Inflammasomes represent stress-induced protein complexes. They are critically involved in acute and chronic inflammation through caspase-1-mediated activation of pro-inflammatory cytokines. Here, we demonstrate that Nrf2 is a positive regulator of the NLRP3 inflammasome. In contrast, Nrf2-activating compounds, including the anti-inflammatory drug dimethyl fumarate (DMF), inhibit inflammasome activation. Both effects are independent of the transcriptional activity of Nrf2 and, at least in part, not interdependent. On the other hand, NLRP3 inflammasome activation induces a rapid and partly caspase-1- and Keap1-independent degradation of Nrf2. These data argue against a simultaneous activation of both stress-related pathways. Finally, we provide evidence that the cross-regulation of both pathways is controlled by a physical interaction between the Nrf2/Keap1 and NLRP3 complexes.
authors.affiliation: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Martha
authors.initials: M
authors.lastname: Garstkiewicz
authors.affiliation: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Gerhard E
authors.initials: GE
authors.lastname: Strittmatter
authors.affiliation: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Serena
authors.initials: S
authors.lastname: Grossi
authors.affiliation: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Sand
authors.affiliation: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Fenini
authors.affiliation: Department of Biology, Institute of Molecular Health Sciences, Zurich, Switzerland.
authors.forename: Sabine
authors.initials: S
authors.lastname: Werner
authors.affiliation: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Lars E
authors.initials: LE
authors.lastname: French
authors.affiliation: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Hans-Dietmar
authors.initials: HD
authors.lastname: Beer
mesh_terms: D000818:Animals; D020170:Caspase 1 / Q000378:metabolism; D016207:Cytokines / Q000276:immunology; D000069462:Dimethyl Fumarate / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D058847:Inflammasomes / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D007249:Inflammation; D015603:Keratinocytes; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016207:Cytokines; D058847:Inflammasomes; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C495636:Nfe2l2 protein, mouse; C492716:Nlrp3 protein, mouse; D020170:Caspase 1; D000069462:Dimethyl Fumarate
keywords: Inflammasomes; Inflammation; Inflammatory diseases; Nrf2; Nrf2 activators