Glutathione Reductase Promotes Fungal Clearance and Suppresses Inflammation During Systemic Candida albicans Infection

Abstract

Abstract Glutathione reductase (Gsr) catalyzes the reduction of glutathione disulfide (GSSG) to glutathione (GSH), a major cellular antioxidant. We have previously shown that Gsr facilitates neutrophil bactericidal activities and is pivotal for host defense against bacterial pathogens. However, it is unclear whether Gsr is required for immune defense against fungal pathogens. It is also unclear whether Gsr plays a role in immunological functions outside of neutrophils. To address these questions, we studied the effect of Gsr knockout on immune defense against C. albicans. Upon infection by C. albicans, Gsr−/− mice displayed dramatically increased fungal burden in the kidneys, cytokine and chemokine storm, striking neutrophil infiltration and histological abnormalities in both the kidneys and hearts, and substantially elevated mortality. Large fungal foci surrounded by massive numbers of neutrophils were detected outside of glomerulus in the kidneys of Gsr−/− mice but were not found in wildtype mice. Examination of the neutrophils and macrophages of Gsr−/− mice also revealed several defects, including compromised phagocytosis, attenuated respiratory burst, and impaired fungicidal activity in Gsr−/− neutrophils in vitro. Moreover, upon C. albicans stimulation, Gsr−/− macrophages produced increased levels of inflammatory cytokines and exhibited elevated p38 and JNK activities, at least in part due to lower mitogen-activated protein kinase phosphatase (Mkp)-1 activity and greater Syk activity. Thus, Gsr-mediated redox regulation was found to be crucial for fungal clearance by neutrophils and the proper control of the inflammatory response by macrophages during host defense against fungal challenge.