The sodium/hydrogen exchanger: a possible mediator of immunity

Immune cells such as macrophages and neutrophils provide the first line of defence of the immune system using phagocytosis, cytokine and chemokine synthesis and release, as well as Reactive Oxygen Species (ROS) generation. Many of these functions are positively coupled with cytoplasmic pH (pHi) and/or phagosomal pH (pHp) modification; an increase in pHi represents an important signal for cytokine and chemokine release, whereas a decrease in pHp can induce an efficient antigen presentation. However, the relationship between pHi and ROS generation is not well understood. In immune cells two main transport systems have been shown to regulate pHi: the Na+/H+ Exchanger (NHE) and the plasmalemmal V-type H+ ATPase. NHE is a family of proteins which exchange Na+ for H+ according to their concentration gradients in an electroneutral manner. The exchanger also plays a key role in several other cellular functions including proliferation, differentiation, apoptosis, migration, and cytoskeletal organization. Since not much is known on the relationship between NHE and immunity, this review outlines the contribution of NHE to different aspects of innate and adaptive immune responses such as phagosomal acidification, NADPH oxidase activation and ROS generation, cytokine and chemokine release as well as T cell apoptosis. The possibility that several pro-inflammatory diseases may be modulated by NHE activity is evaluated.