Nuclear factor E2-related factor-2 (Nrf2) is required for NLRP3 and AIM2 inflammasome activation [Signal Transduction]

May 5th, 2014 by Zhao, C., Gillette, D. D., Li, X., Zhang, Z., Wen, H.

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 level in a Myd88-dependent manner. When compared to wild-type controls, Nrf2-deficient (Nrf2−/−) macrophages showed decreased maturation and secretion of caspase-1 and IL-1β and reduced 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 ROS-induced NLRP3 activation also required Nrf2. Nrf2−/− mice showed a dramatic decrease in immune cell recruitment in alum-induced peritonitis, which is a typical IL-1 signaling-dependent inflammation animal model. This work discovered a critical pro-inflammatory effect of Nrf2 by mediating inflammasome activation.