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This Article Full Text Full Text (PDF) All Versions of this Article: 297/3/C621    most recent 00651.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Sanmun, D. Articles by Fadeel, B. PubMed PubMed Citation Articles by Sanmun, D. Articles by Fadeel, B.

EXTRACELLULAR MATRIX, CELL INTERACTIONS

Involvement of a functional NADPH oxidase in neutrophils and macrophages during programmed cell clearance: implications for chronic granulomatous disease

¹Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; ²Thalassemia Research Center, Institute of Sciences and Technology for Research and Development, Mahidol University, Salaya Campus, Nakhonpathom, Thailand; ³Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania; ⁴Sachs' Children's Hospital, and ⁵Department of Clinical Science and Education, Karolinska Institutet at Stockholm South Hospital, and ⁶Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden

Submitted 22 December 2008 ; accepted in final form 30 June 2009

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.

inflammation; apoptosis; phagocytosis; phosphatidylserine