Catalase S-Glutathionylation by NOX2 and Mitochondrial-Derived ROS Adversely Affects Mice and Human Neutrophil Survival
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ORIGINAL ARTICLE
Catalase S-Glutathionylation by NOX2 and Mitochondrial-Derived ROS Adversely Affects Mice and Human Neutrophil Survival Sheela Nagarkoti,1 Megha Dubey,1 Samreen Sadaf,1 Deepika Awasthi,1 Tulika Chandra,2 Kumaravelu Jagavelu,1 Sachin Kumar,1 and Madhu Dikshit3,4
Abstract— Neutrophil survival and oxidative stress during inflammatory conditions are linked to tissue damage. The present study explores less understood role of catalase, the enzyme catalysing hydrogen peroxide decomposition, in neutrophil survival/death. Importantly, inhibition of catalase activity following S-glutathionylation in the PMA, NO, or zymosan-activated neutrophils or treatment with catalase inhibitor led to neutrophil death. On the contrary, introducing reducing environment by TCEP rescued catalase activity and significantly improved neutrophil survival. Furthermore, augmentation in ROS generation by NOX-2 activation or induction of mitochondrial ROS by Antimycin-A induced catalase S-glutathionylation and cell death, which was prevented in the neutrophil cytosolic factor1 (NCF-1-/-) cells or was rescued by MitoTEMPO, a mitochondrial ROS scavenger, thus, suggesting a correlation between catalase Sglutathionylation/activity inhibition and reduced neutrophil survival. Altogether, enhanced NOX2 activation/mitochondrial dysfunction led to reduced survival of human and mice neutrophils, due to H2O2 accumulation, S-glutathionylation of catalase, and reduction in its enzymatic activity. The present study thus demonstrated mitigation of catalase activity under oxidative stressimpacted neutrophil survival. KEY WORDS: Neutrophil survival; NADPH oxidase; Mitochondrial ROS; Catalase S-glutathionylation; MitoTEMPO; Antimycin-A; 3-aminotriazole.
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10753-019-01093-z) contains supplementary material, which is available to authorized users. 1
Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, India 2 King George’s Medical University, Lucknow, India 3 Present Address: THSTI National Chair, NCR Biotech Science Cluster, Translational Health Science and Technology Institute, 3rd Milestone, Faridabad–Gurgaon Expressway, Faridabad, Haryana 121001, India 4 To whom correspondence should be addressed at THSTI National Chair, NCR Biotech Science Cluster, Translational Health Science and Technology Institute, 3rd Milestone, Faridabad–Gurgaon Expressway, Faridabad, Haryana 121001, India. E-mail: [email protected]
INTRODUCTION Neutrophils are the crucial player of innate immunity; however, their uncontrolled activation exuberate inflammatory conditions. Short life span of neutrophils with spontaneous programmed cell death endorses efficient resolution of acute and chronic inflammation. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) generation by neutrophils exert robust cytotoxic response against ingested pathogens. In addition, dysregulation of neutrophil production and its turnover resolutely contribute
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