title: Local Generation of Kynurenines Mediates Inhibition of Neutrophil Chemotaxis by Uropathogenic Escherichia coli.
abstract: During epithelial infections, pathogenic bacteria employ an array of strategies to attenuate and evade host immune responses, including the influx of polymorphonuclear leukocytes (PMN; neutrophils). Among the most common bacterial infections in humans are those of the urinary tract, caused chiefly by uropathogenic Escherichia coli (UPEC). During the establishment of bacterial cystitis, UPEC suppresses innate responses via multiple independent strategies. We recently described UPEC attenuation of PMN trafficking to the urinary bladder through pathogen-specific local induction of indoleamine 2,3-dioxygenase (IDO), a tryptophan catabolic enzyme previously shown to have regulatory activity only in adaptive immunity. Here, we investigated the mechanism by which IDO induction attenuates PMN migration. Local tryptophan limitation, by which IDO is known to influence T cell longevity and proliferation, was not involved in its effect on PMN trafficking. Instead, metabolites in the IDO pathway, particularly L-kynurenine, directly suppressed PMN transepithelial migration and induced an attached, spread morphology in PMN both at rest and in the presence of chemotactic stimuli. Finally, kynurenines represent known ligands of the mammalian aryl hydrocarbon receptor (AHR), and UPEC infection of Ahr(-/-)mice recapitulated the derepressed PMN recruitment observed previously in Ido1(-/-)mice. UPEC therefore suppresses neutrophil migration early in bacterial cystitis by eliciting an IDO-mediated increase in local production of kynurenines, which act through the AHR to impair neutrophil chemotaxis.
authors: Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA.
authors: Jennifer A
authors: JA
authors: Loughman
authors: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors: Melanie L
authors: ML
authors: Yarbrough
authors: Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA.
authors: Kristin M
authors: KM
authors: Tiemann
authors: Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA dhunstad@wustl.edu.|Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors: David A
authors: http://orcid.org/0000-0002-9848-0975
authors: DA
authors: Hunstad
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002633:Chemotaxis / Q000502:physiology*; D004847:Epithelial Cells / Q000382:microbiology / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism; D007737:Kynurenine / Q000378:metabolism*; D051379:Mice; D009504:Neutrophils / Q000382:microbiology / Q000502:physiology*; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D001743:Urinary Bladder / Q000166:cytology; D056689:Uropathogenic Escherichia coli
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007737:Kynurenine; D018336:Receptors, Aryl Hydrocarbon; C484722:Ahr protein, mouse