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Exposure of to bactericidal hypochlorous acid during neutrophil phagocytosis is compromised in cystic fibrosis. | LitMetric

Exposure of to bactericidal hypochlorous acid during neutrophil phagocytosis is compromised in cystic fibrosis.

J Biol Chem

Centre for Free Radical Research, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch 8011, New Zealand.

Published: September 2019

AI Article Synopsis

  • Myeloperoxidase is an important antimicrobial protein in neutrophils, but its significance is often underestimated since individuals lacking it appear healthy.
  • The study discovered that myeloperoxidase, using superoxide, converts chloride into hypochlorous acid (HOCl), which effectively kills bacteria by oxidizing their glutathione (GSH).
  • The research also found that in cystic fibrosis (CF) patients, HOCl production in neutrophils is initially normal but decreases over time, correlating with reduced bacterial killing efficacy.

Article Abstract

Myeloperoxidase is a major neutrophil antimicrobial protein, but its role in immunity is often overlooked because individuals deficient in this enzyme are usually in good health. Within neutrophil phagosomes, myeloperoxidase uses superoxide generated by the NADPH oxidase to oxidize chloride to the potent bactericidal oxidant hypochlorous acid (HOCl). In this study, using phagocytosis assays and LC-MS analyses, we monitored GSH oxidation in to gauge their exposure to HOCl inside phagosomes. Doses of reagent HOCl that killed most of the bacteria oxidized half the cells' GSH, producing mainly glutathione disulfide (GSSG) and other low-molecular-weight disulfides. Glutathione sulfonamide (GSA), a HOCl-specific product, was also formed. When neutrophils phagocytosed , half of the bacterial GSH was lost. Bacterial GSA production indicated that HOCl had reacted with the bacterial cells, oxidized their GSH, and was sufficient to be solely responsible for bacterial killing. Inhibition of NADPH oxidase and myeloperoxidase lowered GSA formation in the bacterial cells, but the bacteria were still killed, presumably by compensatory nonoxidative mechanisms. Of note, bacterial GSA formation in neutrophils from patients with cystic fibrosis (CF) was normal during early phagocytosis, but it was diminished at later time points, which was mirrored by a small decrease in bacterial killing. In conclusion, myeloperoxidase generates sufficient HOCl within neutrophil phagosomes to kill ingested bacteria. The unusual kinetics of phagosomal HOCl production in CF neutrophils confirm a role for the cystic fibrosis transmembrane conductance regulator in maintaining HOCl production in neutrophil phagosomes.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737234PMC
http://dx.doi.org/10.1074/jbc.RA119.009934DOI Listing

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