Involvement of a functional NADPH oxidase in neutrophils and macrophages during programmed cell clearance: implications for chronic granulomatous disease.
Resolution of inflammation requires clearance of activated neutrophils by macrophages in a manner that prevents injury to adjacent tissues. Surface changes, including phosphatidylserine (PS) exposure, may target neutrophils for phagocytosis. In this study, we show that externalization of PS is defective in phorbol myristate acetate (PMA)-activated neutrophils obtained from chronic granulomatous disease (CGD) patients with mutations in components of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Moreover, activated neutrophils from CGD patients failed to undergo clearance upon cocultivation with macrophages from normal donors. In line with these results, treatment of donor neutrophils with diphenyleneiodonium (DPI), an inhibitor of NADPH oxidase, blocked PMA-induced PS oxidation and externalization and prevented their engulfment by macrophages. Furthermore, primary macrophages from CGD patients or human gp91(phox)-deficient PLB-985 cells differentiated into macrophage-like cells were defective for engulfment of apoptotic target cells. Pretreatment of normal macrophages with DPI also suppressed the subsequent ingestion of PS-positive target cells. Together, these data demonstrate that NADPH oxidase plays an important role in the process of macrophage disposal of target cells (programmed cell clearance). Thus we speculate that the lack of a functional NADPH oxidase results in impaired neutrophil clearance and the exaggerated inflammation that is characteristic for CGD.
Sanmun
Duangmanee
D
Div. of Molecular Toxicology, Inst. of Environmental Medicine, Nobels väg 13, Karolinska Institutet, 171 77 Stockholm, Sweden.
Witasp
Erika
E
Jitkaew
Siriporn
S
Tyurina
Yulia Y
YY
Kagan
Valerian E
VE
Ahlin
Anders
A
Palmblad
Jan
J
Fadeel
Bengt
B
D000293:Adolescent; D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000502:physiology*; D045744:Cell Line, Tumor; D002648:Child; D005260:Female; D006105:Granulomatous Disease, Chronic / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000502:physiology*; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism*; D009504:Neutrophils / Q000166:cytology / Q000502:physiology*; D010084:Oxidation-Reduction; D010743:Phospholipids
D010743:Phospholipids; D019255:NADPH Oxidases