Hypoxia Selectively Inhibits Respiratory Burst Activity and Killing of Staphylococcus aureus in Human Neutrophils

Naomi N. McGovern, Andrew S. Cowburn, Linsey Porter, Sarah R. Walmsley, Charlotte Summers, Alfred A. R. Thompson, Sadia Anwar, Lisa C. Willcocks, Moira K. B. Whyte, Alison M. Condliffe*, Edwin R. Chilvers

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Neutrophils play a central role in the innate immune response and a critical role in bacterial killing. Most studies of neutrophil function have been conducted under conditions of ambient oxygen, but inflamed sites where neutrophils operate may be extremely hypoxic. Previous studies indicate that neutrophils sense and respond to hypoxia via the ubiquitous prolyl hydroxylase/hypoxiainducible factor pathway and that this can signal for enhanced survival. In the current study, human neutrophils were shown to upregulate hypoxia-inducible factor (HIF)-1 alpha-dependent gene expression under hypoxic incubation conditions (3 kPa), with a consequent substantial delay in the onset of apoptosis. Despite this, polarization and chemotactic responsiveness to IL-8 and fMLP were entirely unaffected by hypoxia. Similarly, hypoxia did not diminish the ability of neutrophils to phagocytose serumopsonized heat-killed streptococci. Of the secretory functions examined, IL-8 generation was preserved and elastase release was enhanced by hypoxia. Hypoxia did, however, cause a major reduction in respiratory burst activity induced both by the soluble agonist fMLP and by ingestion of opsonized zymosan, without affecting expression of the NADPH oxidase subunits. Critically, this reduction in respiratory burst activity under hypoxia was associated with a significant defect in the killing of Staphylococcus aureus. In contrast, killing of Escherichia coli, which is predominantly oxidase independent, was fully preserved under hypoxia. In conclusion, these studies suggest that although the NADPH oxidase-dependent bacterial killing mechanism may be compromised by hypoxia, neutrophils overall appear extremely well adapted to operate successfully under severely hypoxic conditions. The Journal of Immunology, 2011, 186: 453-463.

Original languageEnglish
Pages (from-to)453-463
Number of pages11
JournalJournal of Immunology
Volume186
Issue number1
DOIs
Publication statusPublished - Jan 2011

Keywords

  • PSEUDOMONAS-AERUGINOSA
  • OXIDATIVE STRESS
  • NADPH OXIDASE
  • APOPTOSIS
  • HIF-1-ALPHA
  • EXPRESSION
  • INDUCTION
  • INFECTION
  • ELASTASE
  • SURVIVAL

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