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DPI Selectively Inhibits Intracellular NADPH Oxidase Activity in Human Neutrophils.

Journal article
Authors Alicia Buck
Felix P Klose
Vignes Venkatakrishnan
Claes Dahlgren
Karin Christenson
Johan Bylund
Published in ImmunoHorizons
Volume 3
Issue 10
Pages 488-497
ISSN 2573-7732
Publication year 2019
Published at Institute of Odontology
Institute of Medicine, Department of Rheumatology and Inflammation Research
Institute of Odontology, Section 3
Pages 488-497
Language en
Links dx.doi.org/10.4049/immunohorizons.1...
www.ncbi.nlm.nih.gov/entrez/query.f...
Subject categories Basic Medicine

Abstract

Neutrophils are capable of producing significant amounts of reactive oxygen species (ROS) by the phagocyte NADPH oxidase, which consists of membrane-bound and cytoplasmic subunits that assemble during activation. Neutrophils harbor two distinct pools of the membrane-localized oxidase components, one expressed in the plasma membrane and one in the membranes of intracellular granules. Assembly of active oxidase at either type of membrane leads to release of extracellular ROS or to the production of ROS inside intracellular compartments, respectively. The cytoplasmic NADPH oxidase subunit p40phox seems selectively critical for the ability to generate intracellular ROS, and the recent characterization of patients with p40phox deficiency implies that selective loss of intracellular neutrophil ROS leads to disease with pronounced hyperinflammatory features, suggesting that these ROS are critical for regulation of inflammation. This study aimed at characterizing two pharmacological NADPH oxidase inhibitors, the newly described GSK2795039 and the widely used diphenyleneiodonium (DPI), focusing on their abilities to inhibit human neutrophil ROS production extra- and intracellularly. Whereas GSK2795039 blocked extra- and intracellular NADPH oxidase activity equally, DPI was found to selectively interfere with intracellular ROS production. Selectivity for the intracellular NADPH oxidase was evident as a lower IC50 value, faster onset, and irreversibility of inhibition. We found no evidence of direct interactions between DPI and p40phox, but the selectivity of DPI confirms that regulation of NADPH oxidase activity in neutrophils differs depending on the subcellular localization of the enzyme. This information may be used to pharmacologically mimic p40phox deficiency and to further our understanding of how intracellular ROS contribute to health and disease.

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