Non-Classical Roles of NADPH-Oxidase Dependent Reactive Oxygen Species in Phagocytes

Abstract

Phagocytes are classically known to utilize the NADPH-oxidase dependent Reactive Oxygen Species (ROS) release during host defense for clearance of pathogenic organisms. Insufficient activation of the oxidase, as in Chronic Granulomatous Disease, can lead to inadequate elimination of pathogens and can cause severe, life threatening infections. In this review, we present and discuss non-classical functions of the NADPH oxidase and ROS in phagocytes. We describe mechanisms by which the NADPH oxidase and ROS play regulatory roles in intracellular signal transduction, affecting various immune cell functions such as migration, survival, cytokine / chemokine secretion and cell adhesion. Specifically, we discuss redox dependent post-translational protein modifications such as glutathionylation and oxidation, which affect function of various proteins including actin, protein tyrosine kinases and phosphatases, Ras, and transcription factors such as NFκB, and hence can modulate cell signaling and function. In addition, we describe novel mechanisms by which the electrogenic function of the NADPH oxidase can regulate phagocyte signaling via modulating membrane charge potential and controlling membrane localization of charge sensitive enzymes and proteins. Finally, implications of these mechanisms on the pathogenesis of Chronic Granulomatous Disease are discussed.