Local generation of kynurenines mediates inhibition of neutrophil chemotaxis by uropathogenic Escherichia coli

Jennifer A. Loughman, Melanie L. Yarbrough, Kristin M. Tiemann, David A. Hunstad

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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.

Original languageEnglish
Pages (from-to)1176-1183
Number of pages8
JournalInfection and immunity
Volume84
Issue number4
DOIs
StatePublished - Apr 1 2016

Fingerprint

Dive into the research topics of 'Local generation of kynurenines mediates inhibition of neutrophil chemotaxis by uropathogenic Escherichia coli'. Together they form a unique fingerprint.

Cite this