Glutathione reductase is essential for host defense against bacterial infection

Abstract

Glutathione reductase (Gsr)1 catalyzes the reduction of glutathione disulfide to glutathione, a major cellular antioxidant. We have recently shown that Gsr is essential for host defense against the Gram-negative bacteria Escherichia coli in a mouse model of sepsis. While we have demonstrated that Gsr is required for sustaining the oxidative burst and the development of neutrophil extracellular traps, the role of Gsr in other phagocytic functions remains unclear. It is also unclear whether Gsr-deficient mice exhibit host defense defects against Gram-positive bacteria. In the present study, we characterized the effects of Gsr deficiency on the innate immune responses to a Gram-positive bacterium, group B Streptococcus, and to the Gram-negative bacterial cell wall component lipopolysaccharide (LPS). We found that like, E. coli, group B Streptococcus resulted in a substantially more robust cytokine response and a markedly higher morbidity and mortality in Gsr-deficient mice than in wildtype mice. The increased morbidity and mortality were associated with greater bacterial burden in the Gsr-deficient mice. Interestingly, Gsr-deficient mice did not exhibit a greater sensitivity to LPS than did wildtype mice. Analysis of the neutrophils of Gsr-deficient mice revealed impaired phagocytosis. In response to thioglycollate stimulation, Gsr-deficient mice mobilized far fewer phagocytes, including neutrophils, macrophages, and eosinophils, into their peritoneal cavities than did wildtype mice. The defective phagocyte mobilization is associated with profound oxidation and aggregation of ascitic proteins, particularly albumin. Our results indicate that the oxidative defense mechanism mediated by Gsr is required for an effective innate immune response against bacteria, likely by preventing phagocyte dysfunction due to oxidative damage.

Free Radicals and Reactive Oxygen Species

“…In agreement with the implications of this reasoning, the mice lacking glutathione reductase proved to be more susceptible to bacterial infections in vivo and less able to eliminate (kill) bacteria (Yan et al, 2012(Yan et al, , 2013. Further, the vitality observed in the mice expressing no glutathione reductase was observed in the specific pathogen-free environs of vivariums.…”

Reactive oxygen species and antioxidant defense in human gastrointestinal diseases

“…The dimeric nature of the enzyme is critical for its function, because both subunits contribute essential residues to the constitution of the active site. It is noteworthy that different GR isoforms are found not only in the cytosol, but also in the mitochondrial matrix and chloroplasts 22, 57. Functionally, GR is an NADPH:GSSG oxidoreductase 58 .…”

Melatonin restores neutrophil functions and prevents apoptosis amid dysfunctional glutathione redox system

“…Besides, GR plays a central role in the regeneration of GSH levels by reducing GSSG, thus maintaining the intracellular GSH pool and redox balance. 37 GR is essential for host defense against the Escherichia coli in a mouse model of sepsis. 45 The GR-null mice exhibited high mortality and a robust cytokine storm than the wild type.…”

“…32 A significantly reduced neutrophil phagocytic oxidative burst is reported in GR-deficient mice as well as in GR-deficient human subjects. 36,37 In addition, altered GSH level and/or GR activity are also observed in various clinical conditions that are associated with chronic inflammation and impaired immune functions such as autoimmunity, Alzheimer's and Parkinson's diseases, diabetes, and microbial -infections. 38,39 Reduced GSH levels in neutrophils from Burkholderia pseudomallei infected diabetic patients show defective phagocytosis, chemotaxis, and oxidative killing process as compared to healthy individuals.…”