Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 47, Issue 5, Pages 806-817Publisher
WILEY
DOI: 10.1002/eji.201646665
Keywords
Inflammasomes; Inflammation; Inflammatory diseases; Nrf2; Nrf2 activators
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Funding
- Helmut Horten Stiftung
- Gottfried und Julia Bangerter-Rhyner-Stiftung
- Wilhelm Sander-Stiftung [2015.035.1]
- Promedica Stiftung
- Swiss National Science Foundation [31003A_132450]
- Swiss National Science Foundation (SNF) [31003A_132450] Funding Source: Swiss National Science Foundation (SNF)
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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 Keap1independent 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.
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