Nuclear Factor E2-related Factor-2 (Nrf2) Is Required for NLRP3 and AIM2 Inflammasome Activation

• Published in: The Journal of biological chemistry 2014-06, Vol.289 (24), p.17020-17029
• Main Authors: Zhao, Changcheng, Gillette, Devyn D., Li, Xinghui, Zhang, Zhibin, Wen, Haitao
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; CARD Signaling Adaptor Proteins - genetics; CARD Signaling Adaptor Proteins - metabolism; Carrier Proteins - genetics; Carrier Proteins - metabolism; Caspase 1 - genetics; Caspase 1 - metabolism; DNA-Binding Proteins; Immunology; Inflammasomes - metabolism; Interleukin-1beta - genetics; Interleukin-1beta - metabolism; Macrophage Activation; Macrophages - immunology; Macrophages - metabolism; Mice; Mice, Inbred C57BL; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - metabolism; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; NLR Family, Pyrin Domain-Containing 3 Protein; Nuclear Proteins - genetics; Nuclear Proteins - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.563114

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. Background: A subgroup of the NLR (nucleotide binding domain, leucine-rich repeat-containing) proteins and a non-NLR protein AIM2 are key mediators of the inflammasome. Results: Cells lacking Nrf2 are defective in the activation of the NLRP3 and AIM2 inflammasome but not the NLRC4 inflammasome. Conclusion: Nrf2 is an essential mediator of NLRP3 and AIM2 inflammasome activation. Significance: Nrf2 plays a proinflammatory role by enhancing inflammasome activation.