The Journal of Experimental Medicine
ThymUS '08
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Published online 31 July 2006 doi:10.1084/jem.20052069
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 8, 1927-1937
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ARTICLE

 Neutrophils from p40phox–/– mice exhibit severe defects in NADPH oxidase regulation and oxidant-dependent bacterial killing

Chris D. Ellson1, Keith Davidson1, G. John Ferguson1, Rod O'Connor2, Len R. Stephens1, and Phillip T. Hawkins1

1 Inositide Laboratory and 2 Laboratory of Molecular Signalling, The Babraham Institute, Babraham Research Campus, Cambridge CB2 4AT, UK

CORRESPONDENCE Phillip T. Hawkins: phillip.hawkins{at}bbsrc.ac.uk

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 gp91phox, p22phox, p47phox, p67phox, p40phox, and rac-2. Mutations in each of the phox components, except p40phox, have been described in cases of chronic granulomatous disease (CGD), defining their essential role in oxidase function. We sought to establish the role of p40phox by investigating the NADPH oxidase responses of neutrophils isolated from p40phox–/– mice. In the absence of p40phox, the expression of p67phox is reduced by ~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 ~97, 85, 84, 75, and 30%, respectively. The defect in ROS production by p40phox–/– 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 p40phox as an essential component in bacterial killing.

Abbreviations used: BMN, bone marrow–derived neutrophil; CGD, chronic granulomatous disease; DPI, diphenyleneiodonium chloride; HRP, horseradish peroxidase; MAPK, mitogen-activated protein kinase; NADPH, reduced nicotinamide adenine dinucleotide phosphate; NBT, nitroblue tetrazolium; PI3K, phosphoinositide 3-kinase; ROS, reactive oxygen species.

C.D. Ellson and K. Davidson contributed equally to this work.


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