IκBζ controls NLRP3 inflammasome activation via upregulation of the Nlrp3 gene

Abstract Inflammasome activation induces the maturation and secretion of interleukin (IL)-1β and -18, and is dependent on NF-κB signaling to induce the transcription of the inflammasome components, called the priming step. This study elucidated the role of IκBζ, an atypical IκBs (inhibitor of κB) and a coactivator of NF-κB target genes, on the activation of inflammasome. Bone marrow-derived macrophages (BMDMs) that originated from IκBζ-encoding Nfkbiz gene depletion mice presented a defect in NLRP3 inflammasome activation. In addition, the Nfkbiz+/− and Nfkbiz−/− mice significantly attenuated serum IL-1β secretion in response to a monosodium urate injection, a NLRP3 trigger, when compared with Nfkbiz−+/+ mice. The lack of IκBζ in BMDMs produced a disability in the expression of Nlrp3 and pro-Il1β mRNAs during the priming step. In addition, ectopic IκBζ expression enhanced the Nlrp3 promoter activity, and Nlrp3 and pro-Il1β transcription. Overall, IκBζ controlled the activation of NLRP3 inflammasome by upregulating the Nlrp3 gene during the priming step.