The NLRP 3 inflammasome affects DNA damage responses after oxidative and genotoxic stress in dendritic cells

• Published in: European journal of immunology 2013-08, Vol.43 (8), p.2126-2137
• Main Authors: Licandro, Ginevra, Ling Khor, Hwei, Beretta, Ottavio, Lai, Junyun, Derks, Heidi, Laudisi, Federica, Conforti‐Andreoni, Cristina, Liang Qian, Hong, Gee Teng, Gim, Ricciardi‐Castagnoli, Paola, Mortellaro, Alessandra
• Format: Article
• Language: English
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201242918

The NOD‐like receptor (NLR) family pyrin domain‐containing 3 ( NLRP 3) 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 NLRP 3 inflammasome in murine dendritic cells ( DC s) in response to monosodium urate ( MSU ) crystals. Using a transcriptomic approach, we found that DC s from N lrp3 −/− mice responded to MSU with differential expression of genes involved in the DNA damage response and apoptosis. Upon exposure to MSU or other ROS ‐mobilizing stimuli (rotenone and γ‐radiation), DNA fragmentation was markedly ameliorated in N lrp3 −/− and casp‐1 −/− DC s compared with WT DC s. Moreover, N lrp3 −/− DC s 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 DC s. Basal DNA repair capacity in WT DC s resulted in activation and stabilization of p53 in vitro and in vivo, which resulted in increased cell death compared with that in N lrp3 −/− DC s. These data provide the first evidence for the involvement of the NLRP 3 inflammasome in DNA damage responses induced by cellular stress.