The Role of Na+/H+ Exchanger Isoform 1 in Inflammatory Responses: Maintaining H+ Homeostasis of Immune Cells

The Na+/H+ exchangers (NHEs) are a family of membrane transporter proteins which catalyze the electroneutral exchange of one Na+ for one H+ and thus regulate intracellular pH (pH(i)) and cell volume. It is shown that Na+/H+ exchanger isoform 1 (NHE-1), but not other isoforms, is the important mechanism in extruding H+ and regulating pH(i) in the immune system. Immune cells, such as monocytes and neutrophils, generate reactive oxygen species (ROS) and cytokines in response to various stimuli and provide the first line of defense in the immune system. NHE-1 is activated during this respiratory burst and required to maintain an optimal pH(i) for the immune cells. In the central nervous system, NHE-1 is important for microglial (macrophage) activation and participates in the inflammatory response under pathological conditions including cerebral ischemia and traumatic brain injury. NHE-1 also affects Ca2+ homeostasis in microglia and contributes to the increase of [Ca2+](i) by coupling to the Na+/Ca2+ exchanger (NCX) stimulation, thus regulating immune cell function and participating in ischemic cell death. A better understanding of the function of NHE-1 in inflammatory responses will provide insight into its role in brain damage under disease conditions.