Beyond the Extra Respiration of Phagocytosis: NADPH Oxidase 2 in Adaptive Immunity and Inflammation

Abstract

Reactive oxygen species (ROS) derived from the phagocyte NADPH oxidase (NOX2) are essential for host defence and immunoregulation. Their levels must be tightly controlled. ROS are required to prevent infection and are used in signalling to regulate several processes that are essential for normal immunity. A lack of ROS then leads to immunodeficiency and autoinflammation. However, excess ROS are also deleterious, damaging tissues by causing oxidative stress. In this review, we focus on two particular aspects of ROS biology: (i) the emerging understanding that NOX2-derived ROS play a pivotal role in the development and maintenance of adaptive immunity and (ii) the effects of excess ROS in systemic disease and how limiting ROS might represent a therapeutic avenue in limiting excess inflammation.

Keywords: CGD; NOX2; ROS; oxidative stress; systemic inflammation.

Figure 1

Structure of NADPH oxidase 2 during resting and activated states. At rest NADPH oxidase 2 (NOX2) is comprised of the membrane bound heterodimer gp91phox-p22phox, and the cytosolic component, comprised of p40phox (24), p47phox (22), p67phox (22) and the GTPase Rac1 (25) or Rac2 (26). Following stimulation, p47phox becomes phosphorylated and the Rac protein becomes GTP-bound, allowing the complex to translocate to the membrane where it can associate with the gp91phox-p22phox heterodimer. Together, this forms the activated complex that generates reactive oxygen species (ROS) by transferring electrons from NADPH.

Figure 2

Imbalanced Reactive Oxygen Species generation can have implications for human health. High levels of Reactive Oxygen Species (ROS) can result in oxidative stress, which can lead to a number of diseases including Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), Alzheimer’s Disease (AD) and Influenza. Alternatively in primary immunodeficiencies, such as Chronic Granulomatous Disease (CGD), where a genetic defect means ROS are not generated, sterile inflammation often develops.