Glutathione Reductase
Facilitates Host Defense by Sustaining Phagocytic Oxidative Burst and Promoting
the Development of Neutrophil Extracellular Traps [2012](IR93)
// - - Begin memo item - - - - - - - - - -
- - - - - - - - - - - - - - - - - - - - - - //
(Memo Item created on May 10, 2012 03:41 PM)
- - - Begin title or keyword:
Glutathione Reductase
Facilitates Host Defense by Sustaining Phagocytic Oxidative Burst and Promoting
the Development of Neutrophil Extracellular Traps
- - - End title or
keyword:
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: yusen.liu@nationwidechildrens.org
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.).
// - - - - - - - - - - - - - - - - - - - -
- - - - - - - - - - - - - End memo item - - //
