Neutrophils from p40phox-/- mice exhibit severe defects in NADPH oxidase regulation and oxidant-dependent bacterial killing.
The generation of reactive oxygen species (ROS) by the reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex plays a critical role in the antimicrobial functions of the phagocytic cells of the immune system. The catalytic core of this oxidase consists of a complex between gp91(phox), p22(phox), p47(phox), p67(phox), p40(phox), and rac-2. Mutations in each of the phox components, except p40(phox), have been described in cases of chronic granulomatous disease (CGD), defining their essential role in oxidase function. We sought to establish the role of p40(phox) by investigating the NADPH oxidase responses of neutrophils isolated from p40(phox-/-) mice. In the absence of p40(phox), the expression of p67(phox) is reduced by approximately 55% and oxidase responses to tumor necrosis factor alpha/fibrinogen, immunoglobulin G latex beads, Staphylococcus aureus, formyl-methionyl-leucyl-phenylalanine, and zymosan were reduced by approximately 97, 85, 84, 75, and 30%, respectively. The defect in ROS production by p40(phox-/-) neutrophils in response to S. aureus translated into a severe, CGD-like defect in the killing of this organism both in vitro and in vivo, defining p40(phox) as an essential component in bacterial killing.
Ellson
Chris D
CD
Inositide Laboratory, The Babraham Institute, Babraham Research Campus, Cambridge CB2 4AT, UK.
Davidson
Keith
K
Ferguson
G John
GJ
O'Connor
Rod
R
Stephens
Len R
LR
Hawkins
Phillip T
PT
D000818:Animals; D001424:Bacterial Infections / Q000276:immunology / Q000382:microbiology; D001772:Blood Cell Count; D002448:Cell Adhesion / Q000187:drug effects; D002454:Cell Differentiation; D005340:Fibrinogen / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D051379:Mice; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D016877:Oxidants / Q000378:metabolism* / Q000494:pharmacology; D010587:Phagocytosis / Q000187:drug effects; D010750:Phosphoproteins / Q000172:deficiency* / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012995:Solubility; D013211:Staphylococcus aureus / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016877:Oxidants; D010750:Phosphoproteins; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C085072:neutrophil cytosol factor 40K; D009240:N-Formylmethionine Leucyl-Phenylalanine; D005340:Fibrinogen; D019255:NADPH Oxidases