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/
hypoxia-inducible factor pathway and that this can signal for enhanced survival. In the current study, human neutrophils were shown to upregulate
hypoxia-inducible factor (HIF)-1α-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 serum-opsonized 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.