Defect in neutrophil function accounts for impaired anti-fungal immunity in kidney dysfunction

Abstract

Abstract Chronic kidney disease is increasingly recognized as a major public health problem, and has a prevalence of 10% in the general population. Accumulation of uremic toxins results in systemic immunosuppression. Sepsis due to microbial infections accounts for 20% of deaths in patients with kidney diseases. Increased susceptibility of uremic patients to invasive fungal infections may attribute to impairment of innate immune defense. However, the molecular mechanisms of impaired anti-fungal immunity in kidney dysfunction are poorly understood. In this study, we have used the mouse model of aristolochic acid nephropathy to investigate the effect of uremia on antifungal immunity. A single IP injection of aristolochic acid I resulted in severe tubulointerstitial injuries accompanied by increased level blood urea nitrogen. Uremic mice showed increased Candida albicans burden in the internal organs following systemic infection. Increased fungal load was not attributed to defect in migration of neutrophils in the infected organs. Uremic condition impaired the ROS production and fungicidal activity of neutrophils. Interestingly, incubation of neutrophils with uremic serum led to impairment of their energy metabolism, indicated by reduced ATP content and lactate production. Neutrophils incubated with uremic serum showed reduced Glut1 protein expression and impaired glucose uptake capacity. Surprisingly, uremic serum inhibited PI3K/AKT pathway leading to aberrant activation of GSK3β in neutrophils. Furthermore, inhibition of GSK3β restored the glucose uptake in neutrophils incubated with uremic serum. These results indicate that uremia suppresses the anti-fungal activity of neutrophils by inhibiting their immunometabolism.