Inhibition of the lymphocyte metabolic switch by the oxidative burst of human neutrophils

Activation of the phagocytic NADPH oxidase (NOX-2) in neutrophils is a critical process in the innate immune system and is associated with elevated local concentrations of superoxide, hydrogen peroxide and hypochlorous acid. Under pathological conditions, NOX-2 activity has been implicated in the development of autoimmunity, indicating a role in modulating lymphocyte effector function. Notably, T cell clonal expansion and subsequent cytokine production requires a metabolic switch from mitochondrial respiration to aerobic glycolysis. Previous studies demonstrate that hydrogen peroxide generated from activated neutrophils suppresses lymphocyte activation but the mechanism is unknown. We hypothesized that activated neutrophils would prevent the metabolic switch and suppress the effector functions of T cells through a hydrogen peroxide-dependent mechanism. To test this, we developed a model co-culture system using freshly isolated neutrophils and lymphocytes from healthy human donors. Extracellular flux analysis was used to assess mitochondrial and glycolytic activity and FACS analysis to assess immune function. The neutrophil oxidative burst significantly inhibited the induction of lymphocyte aerobic glycolysis, caused inhibition of oxidative phosphorylation, and suppressed lymphocyte activation through a hydrogen peroxide-dependent mechanism. The impact of hydrogen peroxide on bioenergetics in the lymphocytes was confirmed using authentic reagent and a redox cycling agent. In s...
Source: Clinical Science - Category: Biomedical Science Authors: Source Type: research