Disease is initiated by autoreactive T cells, which escape negative selection by expressing a second TCR with a different specificity or an altered affinity. Transfer of Ag-specific Treg cells ameliorates the early onset signs of disease but does not prevent the development of long-term chronic pathologies. Altogether, our results suggest that Ag dose directly affects Treg-cell generation and thus, the set-up of T-cell tolerance. “
“The NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome is a cytoplasmic protein complex that mediates inflammatory

responses to a broad array of danger signals. The inflammasome drives caspase-1 activation and promotes secretion of the pro-inflammatory cytokines IL-1β and IL-18, and might also participate in other cellular processes. Here, we tried to identify new pathways regulated by the NLRP3 inflammasome in murine dendritic cells (DCs) Quizartinib mouse in response to monosodium urate (MSU) crystals. Using a transcriptomic approach, we found that DCs from Nlrp3−/− mice responded to MSU with differential expression of genes involved in the DNA damage response and apoptosis. Upon exposure to see more MSU or other ROS-mobilizing stimuli

(rotenone and γ-radiation), DNA fragmentation was markedly ameliorated in Nlrp3−/− and casp-1−/− DCs compared with WT DCs. Moreover, Nlrp3−/− DCs experienced significantly less oxidative DNA damage mediated by ROS. A significant decrease of the expression of several genes involved in double-strand and base-excision DNA repair was observed in WT DCs. Basal DNA repair capacity in WT DCs resulted in activation and stabilization of p53 in vitro and in vivo, which resulted 4��8C in increased cell death compared with that in Nlrp3−/− DCs. These

data provide the first evidence for the involvement of the NLRP3 inflammasome in DNA damage responses induced by cellular stress. Multicellular organisms are constantly exposed to environmental assaults and have evolved several mechanisms that either promote cellular repair or induce cell death in order to maintain tissue integrity. In particular, the immune system has evolved specialized innate cells that mediate recognition of invading microbes and host perturbations to initiate a potent set of defense mechanisms. To this end, innate cells are equipped with a range of surface and intracellular receptors that recognize both microbial-associated molecular patterns and danger-associated molecular patterns (DAMPs). When damage is not repairable, the damaged cells die and release a multitude of poorly defined DAMPs, which in turn elicit an inflammatory response. Inflammation can be both good and bad, depending on the situation. The NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome is a multiprotein complex, which can drive inflammatory responses by promoting the release of IL-1β and IL-18 from innate cells [1].