Pseudomonas aeruginosa sabotages the generation of host proresolving lipid mediators

Becca A. Flitter, Kelli L. Hvorecny, Emiko Ono, Taylor Eddens, Jun Yang, Daniel H. Kwak, Christopher D. Bahl, Thomas H. Hampton, Christophe Morisseau, Bruce D. Hammock, Xinyu Liu, Janet S. Lee, Jay K. Kolls, Bruce D. Levy, Dean R. Madden, Jennifer M. Bomberger

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Recurrent Pseudomonas aeruginosa infections coupled with robust, damaging neutrophilic inflammation characterize the chronic lung disease cystic fibrosis (CF). The proresolving lipid mediator, 15-epi lipoxin A4 (15-epi LXA4 ), plays a critical role in limiting neutrophil activation and tissue inflammation, thus promoting the return to tissue homeostasis. Here, we show that a secreted P. aeruginosa epoxide hydrolase, cystic fibrosis transmembrane conductance regulator inhibitory factor (Cif), can disrupt 15-epi LXA4 transcellular biosynthesis and function. In the airway, 15-epi LXA4 production is stimulated by the epithelialderived eicosanoid 14,15-epoxyeicosatrienoic acid (14,15-EET). Cif sabotages the production of 15-epi LXA4 by rapidly hydrolyzing 14,15-EET into its cognate diol, eliminating a proresolving signal that potently suppresses IL-8-driven neutrophil transepithelial migration in vitro. Retrospective analyses of samples from patients with CF supported the translational relevance of these preclinical findings. Elevated levels of Cif in bronchoalveolar lavage fluid were correlated with lower levels of 15-epi LXA4 , increased IL-8 concentrations, and impaired lung function. Together, these findings provide structural, biochemical, and immunological evidence that the bacterial epoxide hydrolase Cif disrupts resolution pathways during bacterial lung infections. The data also suggest that Cif contributes to sustained pulmonary inflammation and associated loss of lung function in patients with CF.

Original languageEnglish (US)
Pages (from-to)136-141
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number1
DOIs
StatePublished - Jan 3 2017

Keywords

  • Inflammation
  • LipoxinC
  • Pseudomonas aeruginosa|epoxide hydrolase
  • Ystic fibrosis

ASJC Scopus subject areas

  • General

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    Flitter, B. A., Hvorecny, K. L., Ono, E., Eddens, T., Yang, J., Kwak, D. H., Bahl, C. D., Hampton, T. H., Morisseau, C., Hammock, B. D., Liu, X., Lee, J. S., Kolls, J. K., Levy, B. D., Madden, D. R., & Bomberger, J. M. (2017). Pseudomonas aeruginosa sabotages the generation of host proresolving lipid mediators. Proceedings of the National Academy of Sciences of the United States of America, 114(1), 136-141. https://doi.org/10.1073/pnas.1610242114