Glutathione Reductase Promotes Fungal Clearance and Suppresses Inflammation during Systemic Candida albicans Infection in Mice

Abstract

Glutathione reductase (Gsr) catalyzes the reduction of glutathione disulfide to glutathione, which plays an important role in redox regulation. 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 during immune defense. In this study, we report that Gsr 2/2 mice exhibited markedly increased susceptibility to Candida albicans challenge. Upon C. albicans infection, Gsr 2/2 mice exhibited dramatically increased fungal burden in the kidneys, cytokine and chemokine storm, striking neutrophil infiltration, histological abnormalities in both the kidneys and heart, and substantially elevated mortality. Large fungal foci surrounded by massive numbers of neutrophils were detected outside of the glomeruli in the kidneys of Gsr 2/2 mice but were not found in wild-type mice. Examination of the neutrophils and macrophages of Gsr 2/2 mice revealed several defects. Gsr 2/2 neutrophils exhibited compromised phagocytosis, attenuated respiratory burst, and impaired fungicidal activity in vitro. Moreover, upon C. albicans stimulation, Gsr 2/2 macrophages produced increased levels of inflammatory cytokines and exhibited elevated p38 and JNK activities, at least in part, because of lower MAPK phosphatase (Mkp)-1 activity and greater Syk activity. Thus, Gsr-mediated redox regulation is crucial for fungal clearance by neutrophils and the proper control of the inflammatory response by macrophages during host defense against fungal challenge.

Citrus fruits are rich in flavonoids for immunoregulation and potential targeting ACE2

“…It is further demonstrated that naringin could restrain cytokine storm to a certain extent through inhibiting HMGB1 expression in this study. Additionally, P38 MAPK has an important role in HMGB1-mediated production of proinflammatory cytokines [16] and previous studies indicated inflammation is related to the phosphorylation level of P38 MAPK [17,18]. In this study, naringin pretreatment could attenuate p-P38 MAPK level induced by myocardial I/R injury in rats.…”

MicroRNA-362-5p promotes the proliferation and inhibits apoptosis of trophoblast cells via targeting glutathione-disulfide reductase

“…In addition, GSR is involved the compensating antioxidant pathways dependent on thiol, which maintain the balance between protein dithiol and disulfide [ 28 ]. Except that, GSR protects the host against bacterial pathogen by promoting neutrophil bactericidal activity [ 29 ]. GSR gene in human is located in chromosome 8p12, which is usually lost in cancers [ 28 , 30 , 31 ].…”

Targeting Neurological Manifestations of Coronaviruses by Candidate Phytochemicals: A Mechanistic Approach

“…Naringin also inhibits the expression level of cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS), IL-1β and IL-6 via suppressing high mobility group box 1 (HMGB1) in COVID-19 ( Park et al, 2003 ; Huang et al, 2020a ). It also declined the expression level of p38MAPK to inhibit HMGB1 generation of inflammatory mediators and associated lung injury ( Gil et al, 2016 ; Kim et al, 2019b ). According to the critical destructive role of inflammatory mediators in the neurological signs of COVID-19, naringin seems to be a hopeful anti-inflammatory/antiviral candidate in combating related neuronal manifestations.…”

“…In a recent in silico report by Gorla et al (2020) silymarin, and biochanin A were proposed as bioflavonoids possessing the most acceptable interaction with ACE2/spike protein of SARS-CoV-2. Also, an in silico study indicated that naringenin inhibited 3CLpro chains, thereby may be a promising phytochemical for alleviating neurological symptoms in COVID-19 patients ( Kim et al, 2019b ). Papyriflavonol A as a prenylated flavone inhibited the PLpro and 3CLpro of SARS-CoV at 3.7 and 103.6 µM, respectively ( Park et al, 2017 ).…”