Glutathione Reductase Facilitates Host Defense by Sustaining Phagocytic Oxidative Burst and Promoting the Development of Neutrophil Extracellular Traps [2012](IR93)


Glutathione Reductase Facilitates Host Defense by Sustaining Phagocytic Oxidative Burst and Promoting the Development of Neutrophil Extracellular Traps [2012](IR93)

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Glutathione Reductase Facilitates Host Defense by Sustaining Phagocytic Oxidative Burst and Promoting the Development of Neutrophil Extracellular Traps

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Published online before print January 25, 2012, doi: 10.4049/​jimmunol.1102683
The Journal of Immunology
March 1, 2012
vol. 188 no. 5 2316-2327

Glutathione Reductase Facilitates Host Defense by Sustaining Phagocytic Oxidative Burst and Promoting the Development of Neutrophil Extracellular Traps
Jing Yan*,†, Xiaomei Meng*, Lyn M. Wancket‡, Katherine Lintner*, Leif D. Nelin*, Bernadette Chen*, Kevin P. Francis§, Charles V. Smith¶, Lynette K. Rogers* and Yusen Liu*,‡
- Author Affiliations

*Center for Perinatal Research, The Research Institute at Nationwide Children’s Hospital, Department of Pediatrics, The Ohio State University College of Medicine, Columbus , OH 43205 ;
State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, People’s Republic of China;
Department of Veterinary Bioscience, The Ohio State University College of Veterinary Medicine, Columbus, OH 43221;
§Caliper Life Sciences, Alameda, CA 94501; and
Center for Developmental Therapeutics, Seattle Children’s Research Institute, Seattle, WA 98101
Address correspondence and reprint requests to Dr. Yusen Liu, Center for Perinatal Research, The Research Institute at Nationwide Children’s Hospital, 700 Children’s Drive, Columbus , OH 43205 . E-mail address: [email protected]

Abstract
Glutathione reductase (Gsr) catalyzes the reduction of glutathione disulfide to glutathione, which plays an important role in the bactericidal function of phagocytes. Because Gsr has been implicated in the oxidative burst in human neutrophils and is abundantly expressed in the lymphoid system, we hypothesized that Gsr-deficient mice would exhibit marked defects during the immune response against bacterial challenge. We report in this study that Gsr-null mice exhibited enhanced susceptibility to Escherichia coli challenge, indicated by dramatically increased bacterial burden, cytokine storm, striking histological abnormalities, and substantially elevated mortality. Additionally, Gsr-null mice exhibited elevated sensitivity to Staphylococcus aureus. Examination of the bactericidal functions of the neutrophils from Gsr-deficient mice in vitro revealed impaired phagocytosis and defective bacterial killing activities. Although Gsr catalyzes the regeneration of glutathione, a major cellular antioxidant, Gsr-deficient neutrophils paradoxically produced far less reactive oxygen species upon activation both ex vivo and in vivo. Unlike wild-type neutrophils that exhibited a sustained oxidative burst upon stimulation with phorbol ester and fMLP, Gsr-deficient neutrophils displayed a very transient oxidative burst that abruptly ceased shortly after stimulation. Likewise, Gsr-deficient neutrophils also exhibited an attenuated oxidative burst upon encountering E. coli. Biochemical analysis revealed that the hexose monophosphate shunt was compromised in Gsr-deficient neutrophils. Moreover, Gsr-deficient neutrophils displayed a marked impairment in the formation of neutrophil extracellular traps, a bactericidal mechanism that operates after neutrophil death. Thus, Gsr-mediated redox regulation is crucial for bacterial clearance during host defense against massive bacterial challenge.

Footnotes

This work was supported by National Institutes of Health Grants AI68956 and AI57798 (to Y.L.), HL0075261 (to L.D.N.), and AT006880 (to L.K.R.).

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