Hypoxia selectively inhibits respiratory burst activity and killing of Staphylococcus aureus in human neutrophils.
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.
Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom.
Naomi N
NN
McGovern
Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom.
Andrew S
AS
Cowburn
Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom.
Linsey
L
Porter
Academic Unit of Respiratory Medicine, Department of Infection and Immunity, University of Sheffield, Sheffield, United Kingdom.
Sarah R
SR
Walmsley
Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom.
Charlotte
C
Summers
Academic Unit of Respiratory Medicine, Department of Infection and Immunity, University of Sheffield, Sheffield, United Kingdom.
Alfred A R
AAR
Thompson
Academic Unit of Respiratory Medicine, Department of Infection and Immunity, University of Sheffield, Sheffield, United Kingdom.
Sadia
S
Anwar
Cambridge Institute of Medical Research, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom.
Lisa C
LC
Willcocks
Academic Unit of Respiratory Medicine, Department of Infection and Immunity, University of Sheffield, Sheffield, United Kingdom.
Moira K B
MKB
Whyte
Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom.|Addenbrooke's amd Papworth Hospital Trusts, Cambridge, United Kingdom.
Alison M
AM
Condliffe
Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom.|Addenbrooke's amd Papworth Hospital Trusts, Cambridge, United Kingdom.
Edwin R
ER
Chilvers
D001770:Blood Bactericidal Activity / Q000276:immunology*; D015550:Cell Degranulation / Q000276:immunology; D015687:Cell Hypoxia / Q000276:immunology; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D006801:Humans; D019272:Leukocyte Elastase / Q000378:metabolism; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000097:blood / Q000502:physiology; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000097:blood; D011971:Receptors, Immunologic / Q000097:blood / Q000378:metabolism; D016897:Respiratory Burst / Q000276:immunology*; D013211:Staphylococcus aureus / Q000254:growth & development* / Q000276:immunology* / Q000378:metabolism
D017382:Reactive Oxygen Species; D011971:Receptors, Immunologic; D009240:N-Formylmethionine Leucyl-Phenylalanine; D019255:NADPH Oxidases; D019272:Leukocyte Elastase