Abstract
Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, the enzyme complex responsible for reactive oxygen species (ROS) production, is defective in chronic granulomatous disease (CGD) patients. This enzyme helps in antimicrobial host defense by phagocytes. CGD patients are unable to form neutrophil extracellular traps (NETs), which are composed of granule-derived proteins from neutrophils decorated with decondensed chromatin. Mitochondria have gained attention, being a rich source of flavochrome enzymes due to the presence of several sites for superoxide production. Recently, PPARγ agonists, a mitochondrial ROS inducer, induce mitochondrial ROS formation post-treatment in murine NADPH oxidase knockout models. Mitochondrial ROS is also essential for NOX-independent NETosis. Our study for the first time detects induction of NETosis independent of NADPH oxidase post-treatment with agonists such as pioglitazone and rosiglitazone in CGD subjects. Neutrophils isolated from CGD subjects were treated with pioglitazone and rosiglitazone. After treatment, qualitative analysis of NET formation was done using confocal microscopy after staining with DAPI. Quantitative estimation of extracellular DNA was performed using Sytox green. Mitochondrial ROS production with PPARγ agonist-treated/untreated neutrophils was detected using MitoSOX red. Pioglitazone and rosiglitazone induce significant NET formation in CGD patients. Our data clearly signify the effect of PPARγ agonists in induction of NET formation in CGD cases. Apart from the proposed experimental studies regarding the detailed mechanism of action, controlled trials could provide valuable information regarding the clinical use of pioglitazone in CGD patients as curative HSCT remains challenging in developing countries.
Highlights
Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is a crucial enzyme in antimicrobial host defense by phagocytes and plays an important role in regulating inflammation
We studied for the first time the induction of NETosis by PPARγ agonists such as pioglitazone in chronic granulomatous disease (CGD) subjects
reactive oxygen species (ROS) is an essential component for formation of neutrophil extracellular traps (NETs) that is responsible for clearance of infections by oxidative burst formation
Summary
Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is a crucial enzyme in antimicrobial host defense by phagocytes and plays an important role in regulating inflammation. PPARγ Agonists Induces NETosis producers are xanthine oxidase, nitric oxide synthase, cytochrome P450, and mitochondrial electron transport chain (ETC). Among these ROS producers, mitochondria have drawn increasing attention as they are a rich source of flavochrome enzymes and have several sites for superoxide production [1,2,3]. These NETs traps bacteria, fungus, and protozoa [15,16,17], thereby creating an antimicrobial proteins milieu Various stimuli such as phorbol 12-myristate 13-acetate (PMA), micro-organisms, calcium ionomycin, uric acid, and cytokines/chemokines are known to induce NET formation (NETosis) [18,19,20,21,22]. This study hypothesizes whether NETosis is generated independent of NADPH oxidase after treatment with pioglitazone in CGD cases with varying germline mutations. Mitochondrial ROS production post-PPARγ agonist treatment was studied in CGD subjects with varying germline mutations
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