A functional NADPH oxidase prevents caspase involvement in the clearance of phagocytic neutrophils.
Neutrophils play a prominent role in host defense. Phagocytosis of bacteria leads to the formation of an active NADPH oxidase complex that generates reactive oxygen species for bactericidal purposes. A critical step in the resolution of inflammation is the uptake of neutrophils by macrophages; however, there are conflicting reports on the mechanisms leading to the apoptosis of phagocytic neutrophils. The aim of this study was to clarify the role of effector caspases in these processes. Caspase activity was measured by DEVDase activity assays or immunofluorescence detection of active caspase-3. With normal human and wild-type murine neutrophils there was no caspase activation following phagocytosis of Staphylococcus aureus. However, caspase activity was observed in phagocytic neutrophils with a defective NADPH oxidase, including neutrophils isolated from X-linked gp91(phox) knockout chronic granulomatous disease mice. These results indicate that a functional NADPH oxidase and the generation of oxidants in the neutrophil phagosome prevent the activation of the cytoplasmic caspase cascade.
Wilkie
Rachel P
RP
Department of Pathology, Christchurch School of Medicine and Health Sciences, Christchurch, New Zealand.
Vissers
Margret C M
MC
Dragunow
Mike
M
Hampton
Mark B
MB
D000328:Adult; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008264:Macrophages / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D009504:Neutrophils / Q000201:enzymology* / Q000276:immunology / Q000382:microbiology; D010587:Phagocytosis / Q000276:immunology*; D010718:Phosphatidylserines / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000276:immunology
D061945:Caspase Inhibitors; D008562:Membrane Glycoproteins; D010718:Phosphatidylserines; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D053148:Caspase 3; D020169:Caspases