Recent studies have identified a variety of NLRP3 inflammasome activators

including whole live bacteria, fungal and viral pathogens, as well as various 5-Fluoracil cell line microbial-associated molecular patterns and DAMPs [2]. In addition, cellular stress triggered by factors ranging from oxidative stress to lysosomal damage appears sufficient to activate NLRP3 [3]. The mechanisms by which these molecules of diverse origins and structures can each trigger the NLRP3 inflammasome remain unclear. However, the generation of ROS seems to be a unifying factor, consistently mediating NLRP3 activation across several stimuli [4]. Recently, Zhou and colleagues demonstrated that mitochondrial (mt) ROS are critical for NLRP3 inflammasome activation [5]. Accumulation of ROS-producing mitochondria either by repressing mitochondrial autophagy or by pharmacological inhibition of the mitochondrial electron transport chain resulted in increased release of

IL-1β and IL-18 in response to LPS and ATP, or exposure to monosodium urate (MSU) crystals [5, 6]. The role played by NLRP3 in mediating release of IL-1β is well established, but it remains unclear whether the NLRP3 inflammasome might also have cytokine-independent impacts on host cell responses by acting through alternative pathways. We therefore employed MSU crystals, which elicit robust ROS production and consequently oxidative stress, but not IL-1β release, to examine the role of NLRP3 in non-inflammatory pathways. Here, we show that the NLRP3 click here inflammasome controls cellular responses

to DNA damage after genotoxic stress driven by MSU crystals or γ-radiation. Dendritic cells (DCs) from Nlrp3−/− and casp-1−/− mice exhibited reduced levels of DNA fragmentation as a result of enhanced DNA repair activity mediated by upregulation of double-strand and base-excision DNA repair genes. Moreover, DNA damage triggered the activation of the pro-apoptotic p53 pathway in WT DCs, but less so in Nlrp3−/− and casp-1−/− cells. These findings demonstrate that the NLRP3 inflammasome plays Leukotriene-A4 hydrolase an important role in DNA damage responses (DDR) to oxidative and genotoxic stress, supporting cell death, and ultimately cell death associated inflammation. To identify new cytokine-independent pathways regulated by NLRP3 during oxidative stress, we used MSU crystals, which activate the NLRP3 inflammasome through production of ROS but in the absence of a priming signal do not induce IL-1β and IL-18 production [7, 8]. Cellular transcriptomes of MSU-treated DCs were generated using high-density mouse oligonucleotide Affymetrix gene arrays. Differentially expressed genes (DEGs) were identified in MSU-stimulated DCs from WT and Nlrp3−/− mice compared with their respective untreated controls.