Indeed, we observed that the antioxidant enzymes peroxiredoxin 1 and catalase are upregulated in MSU-treated WT DCs, but remained unchanged in NLRP3-depleted cells. The tumor suppressor protein p53 maintains genomic integrity and is a primary determinant of cell fate following DNA damage; accordingly, the p53 regulatory circuit is mutated in the majority of cancers [19]. In response to cell stress induced DNA damage, p53 regulates the transcription of a multitude of genes responsible for DNA repair, detoxification of ROS, changes in metabolism, and apoptosis [20].

p53 can also modulate these events via transcription-independent mechanisms [21]. When the cell is subjected to environmental stress, cytoplasmic p53 can rapidly move to the mitochondria and promote permeabilization of mitochondrial outer membranes to trigger

the release of pro-apoptotic selleck chemicals llc factors [22]. Moreover, p53 has the capacity to suppress autophagy, which is known to dampen NLRP3 activation and restrict pro-IL-1β synthesis [6, 23]. Following γ-radiation and MSU treatment, we detected a long-lasting p53 phosphorylation in Ser15 and Ser20 in WT cells but not in Nlrp3−/− or casp-1−/− DCs. These data indicate that p53 is more stable in WT DCs and does not readily form complexes with Mdm2, thereby promoting apoptosis of WT DCs. Accordingly, we found that p21, a negative regulator of apoptosis, was upregulated by MSU or γ-radiation in Nlrp3−/− DCs but not WT DCs. Moreover, significantly

Proteasome inhibitor more cell death was induced by MSU treatment in NLRP3-sufficient cells. Pro-apoptotic genes were upregulated in WT DCs but not in Nlrp3−/− DCs, as shown in the transcriptomic data evaluated at 4 h. All together these data suggest that the inflammasome platform is involved in the DDR facilitating the expression and stabilization of p53, thereby inducing caspase-1-dependent cell death, also known as pyroptosis. Pyroptosis is an important mechanism of protection against certain microbial pathogens (Salmonella, Francisella, Yersinia) associated with rapid membrane rupture, release of intracellular content together with IL-1β and IL-18. Similarly to apoptosis, DNA fragmentation also occurs during pyroptosis and Apoptosis antagonist this process requires caspase-1, which triggers a still unknown nuclease activity [24]. However, pyroptosis differs from apoptosis driven by DDR in some aspects. Fragmented DNA is present diffusely in the nucleus and not condensed as during apoptosis [25]. The pro-apoptotic caspase-3, -6, -8, or -9 are not involved in pyroptosis, conversely caspase-1 is not implicated in apoptosis [26]. In addition, mitochondrial integrity is maintained during pyroptosis [27]. Pyroptosis is characterized by plasma membrane breakage, a characteristic that renders this process more similar to necrosis rather than to apoptosis. However, further studies are necessary to elucidate the molecular mechanisms driving pyroptosis.