Glutathione reductase (Gsr) catalyzes the reduction of glutathione disulfide to glutathione. We have recently shown that Gsr is essential for host defense against Escherichia coli in a mouse model of sepsis. While we have demonstrated that Gsr is required for the oxidative burst and the development of NETs, the role of Gsr in other phagocytic functions remains unclear. It is also unclear whether Gsr-null mice exhibit host defense defects against Gram-positive bacteria. Here we characterized the effects of Gsr deficiency on the innate immune responses to group B Streptococcus and LPS. Like E. coli, group B Streptococcus also resulted in a substantially more robust cytokine response, a markedly higher morbidity and mortality, and greater bacterial burden in Gsr-null mice than in wildtype mice. Interestingly, Gsr-deficient mice did not exhibit a greater sensitivity to LPS than did wildtype mice. Analysis of Gsr-null neutrophils revealed an impaired phagocytosis. In response to thioglycollate stimulation, Gsr-null 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 heavy 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.
Glutathione reductase (Gsr) catalyzes the reduction of glutathione disulfide to glutathione. Since Gsr has been implicated in the oxidative burst in human PMN, we hypothesized that Gsr-null mice would exhibit marked defects during the immune response against bacterial challenge. We report here that Gsr-null mice exhibited enhanced susceptibility to E. coli challenge, indicated by dramatically increased bacterial burden, cytokine storm, striking histological abnormalities, and substantially elevated mortality. Examination of the bactericidal functions of the neutrophils from Gsr-null mice in vitro revealed impaired phagocytosis and defective bacterial killing activities. Although Gsr catalyzes the regeneration of glutathione, a major cellular antioxidant, Gsr-null neutrophils paradoxically produced far less reactive oxygen species both ex vivo and in vivo. Unlike wildtype neutrophils that exhibited a sustained oxidative burst upon activation, Gsr-null neutrophils displayed a very transient oxidative burst associated with compromised hexose monophosphate shunt. Likewise, Gsr-null neutrophils also exhibited an attenuated oxidative burst upon encountering E. coli. Moreover, Gsr-null neutrophils displayed a marked impairment in the formation of neutrophil extracellular traps, a bactericidal mechanism which operates after neutrophil death. Thus, Gsr-mediated redox regulation is crucial for bacterial clearance during host defense against massive bacterial challenge.
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