Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8270434 | Free Radical Biology and Medicine | 2014 | 11 Pages |
Abstract
Pseudomonas aeruginosa is responsible for persistent infections in cystic fibrosis patients, suggesting an ability to circumvent innate immune defenses. This bacterium uses the kynurenine pathway to catabolize tryptophan. Interestingly, many host cells also produce kynurenine, which is known to control immune system homeostasis. We showed that most strains of P. aeruginosa isolated from cystic fibrosis patients produce a high level of kynurenine. Moreover, a strong transcriptional activation of kynA (the first gene involved in the kynurenine pathway) was observed upon contact with immune cells and particularly with neutrophils. In addition, using coculture of human neutrophils with various strains of P. aeruginosa producing no (ÎkynA) or a high level of kynurenine (ÎkynU or ÎkynA pkynA), we demonstrated that kynurenine promotes bacterial survival. In addition, increasing the amount kynurenine inhibits reactive oxygen species production by activated neutrophils, as evaluated by chemiluminescence with luminol or isoluminol or SOD-sensitive cytochrome c reduction assay. This inhibition is due neither to a phagocytosis defect nor to direct NADPH oxidase inhibition. Indeed, kynurenine has no effect on oxygen consumption by neutrophils activated by PMA or opsonized zymosan. Using in vitro reactive oxygen species-producing systems, we showed that kynurenine scavenges hydrogen peroxide and, to a lesser extent, superoxide. Kynurenine׳s scavenging effect occurs mainly intracellularly after bacterial stimulation, probably in the phagosome. In conclusion, the kynurenine pathway allows P. aeruginosa to circumvent the innate immune response by scavenging neutrophil reactive oxygen species production.
Keywords
NADPHRLUHRPOCGDIDONBTm.o.i.P. aeruginosaAHRCFUROSnitroblue tetrazoliumindoleamine 2,3-dioxygenasechronic granulomatous diseaseScavengerneutrophil extracellular trapNETFree radicalsSODSuperoxide dismutaseCystic fibrosisTryptophan metabolitesResistanceNADHNeutrophilscolony-forming unitrelative luminescence unitHorseradish peroxidasemultiplicity of infectionkynurenineReactive oxygen speciesaryl hydrocarbon receptor
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Authors
Charlotte Genestet, Audrey Le Gouellec, Hichem Chaker, Benoit Polack, Benoit Guery, Bertrand Toussaint, Marie José Stasia,