The role of chloride anion and CFTR in killing of Pseudomonas aeruginosa by normal and CF neutrophils

Richard G. Painter, Ryan W. Bonvillain, Vincent G. Valentine, Gisele A. Lombard, Stephanie G. LaPlace, William M. Nauseef, Guoshun Wang

Research output: Contribution to journalArticle

97 Scopus citations

Abstract

Chloride anion is essential for myeloperoxidase (MPO) to produce hypochlorous acid (HOCl) in polymorphonuclear neutrophils (PMNs). To define whether chloride availability to PMNs affects their HOCl production and microbicidal capacity, we examined how extracellular chloride concentration affects killing of Pseudomonas aeruginosa (PsA) by normal neutrophils. PMN-mediated bacterial killing was strongly dependent on extracellular chloride concentration. Neutrophils in a chloride-deficient medium killed PsA poorly. However, as the chloride level was raised, the killing efficiency increased in a dose-dependent manner. By using specific inhibitors to selectively block NADPH oxidase, MPO, and cystic fibrosis transmembrane conductance regulator (CFTR) functions, neutrophil-mediated killing of PsA could be attributed to three distinct mechanisms: CFTR-dependent and oxidant-dependent; chloride-dependent but not CFTR- and oxidant-dependent; and independent of any of the tested factors. Therefore, chloride anion is involved in oxidant- and nonoxidant-mediated bacterial killing. We previously reported that neutrophils from CF patients are defective in chlorination of ingested bacteria [1], suggesting that the chloride channel defect might impair the MPO-hydrogen peroxide-chloride microbicidal function. Here, we compared the competence of killing PsA by neutrophils from normal donors and CF patients. The data demonstrate that the killing rate by CF neutrophils was significantly lower than that by normal neutrophils. CF neutrophils in a chloride-deficient environment had only one-third of the bactericidal capacity of normal neutrophils in a physiological chloride environment. These results suggest that CFTR-dependent chloride anion transport contributes significantly to killing PsA by normal neutrophils and when defective as in CF, may compromise the ability to clear PsA.

Original languageEnglish (US)
Pages (from-to)1345-1353
Number of pages9
JournalJournal of Leukocyte Biology
Volume83
Issue number6
DOIs
StatePublished - Jun 1 2008

Keywords

  • Cystic fibrosis
  • Hypochlorous acid
  • Myeloperoxisase

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Cell Biology

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    Painter, R. G., Bonvillain, R. W., Valentine, V. G., Lombard, G. A., LaPlace, S. G., Nauseef, W. M., & Wang, G. (2008). The role of chloride anion and CFTR in killing of Pseudomonas aeruginosa by normal and CF neutrophils. Journal of Leukocyte Biology, 83(6), 1345-1353. https://doi.org/10.1189/jlb.0907658