title: The NLRP3 inflammasome affects DNA damage responses after oxidative and genotoxic stress in dendritic cells.
abstract: 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) 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 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 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.
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology and Research, A*STAR, Biopolis, Singapore. alessandra_mortellaro@immunol.a-star.edu.sg
authors.forename: Ginevra
authors.initials: G
authors.lastname: Licandro
authors.forename: Hwei
authors.initials: H
authors.lastname: Ling Khor
authors.forename: Ottavio
authors.initials: O
authors.lastname: Beretta
authors.forename: Junyun
authors.initials: J
authors.lastname: Lai
authors.forename: Heidi
authors.initials: H
authors.lastname: Derks
authors.forename: Federica
authors.initials: F
authors.lastname: Laudisi
authors.forename: Cristina
authors.initials: C
authors.lastname: Conforti-Andreoni
authors.forename: Hong
authors.initials: H
authors.lastname: Liang Qian
authors.forename: Gim Gee
authors.initials: GG
authors.lastname: Teng
authors.forename: Paola
authors.initials: P
authors.lastname: Ricciardi-Castagnoli
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mortellaro
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D020170:Caspase 1 / Q000235:genetics; D002470:Cell Survival; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D004789:Enzyme Activation; D058847:Inflammasomes / Q000276:immunology*; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D018384:Oxidative Stress; D010538:Peritonitis / Q000139:chemically induced / Q000276:immunology; D017382:Reactive Oxygen Species; D012402:Rotenone / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014475:Uncoupling Agents / Q000494:pharmacology; D014527:Uric Acid / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D002352:Carrier Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D014475:Uncoupling Agents; D012402:Rotenone; D014527:Uric Acid; D020170:Caspase 1
keywords: Apoptosis; DNA damage response; Innate immunity; NLRP3 inflammasome