Regulation of Neutrophil NADPH Oxidase, NOX2: A Crucial Effector in Neutrophil Phenotype and Function

Abstract

Reactive oxygen species (ROS), produced by the phagocyte NADPH oxidase, NOX2, are involved in many leukocyte functions. An excessive or inappropriate ROS production can lead to oxidative stress and tissue damage. On the other hand, an absence of ROS production due to a lack of a functional NADPH oxidase is associated with recurrent infections as well as inflammation disorders. Thus, it is clear that the enzyme NADPH oxidase must be tightly regulated. The NOX2 complex bears both membrane and cytosolic subunits. The membrane subunits constitute the flavocytochrome b558, consisting of gp91phox (Nox2) and p22phox subunits. The cytosolic subunits form a complex in resting cells and are made of three subunits (p47phox, p40phox, p67phox). Upon leukocyte stimulation, the cytosolic subunits and the small GTPase Rac assemble with the flavocytochrome b558 in order to make a functional complex. Depending on the stimulus, the NADPH oxidase can assemble either at the phagosomal membrane or at the plasma membrane. Many studies have explored NOX2 activation; however, how this activation is sustained and regulated is still not completely clear. Here we review the multiple roles of NOX2 in neutrophil functions, with a focus on description of its components and their assembly mechanisms. We then explain the role of energy metabolism and phosphoinositides in regulating NADPH oxidase activity. In particular, we discuss: 1) the link between metabolic pathways and NOX2 activity regulation through neutrophil activation and the level of released ROS, and 2) the role of membrane phosphoinositides in controlling the duration of NOX2 activity.

Neutrophil-specific STAT4 deficiency attenuates atherosclerotic burden and improves plaque stability via reduction in neutrophil activation and recruitment into aortas ofLdlr-/-mice

“…46 Perhaps the most impactful discovery from our Nanostring analysis was the reduced expression of Cybb (NADPH oxidase 2) as this gene is critical to several neutrophil functions related to oxidative burst-dependent mechanisms which are often dysregulated during atherosclerosis. 47 Indeed, our demonstrated correlation of reduced Cybb expression with reduced mitochondrial superoxide production in neutrophils revealed STAT4 as a novel contributor to neutrophil oxidative stress during atherosclerosis. Furthermore, NOX-2 has been demonstrated to play a key role in neutrophil-platelet interactions during vascular inflammation.…”

Inflammation and Neutrophil Oxidative Burst in a Family with NFKB1 p.R157X LOF and Sterile Necrotizing Fasciitis

“…The results of our NADPH oxidase complex subunit quantitation in p.R157X neutrophils were comparable to controls, although minor changes in the complex subunits cannot be excluded by Western blotting [ 5 , 34 ]. We can only speculate that the NFKB1 p.R157X LOF variant may selectively disturb the instant events such as phosphorylation of subunits, protein–protein interactions, protein-lipid interactions, or properties of energy metabolism involved in the carefully regulated oxidative burst [ 35 ].…”

Pathogenesis of Anemia in Canine Babesiosis: Possible Contribution of Pro-Inflammatory Cytokines and Chemokines—A Review

“…This enzyme is also induced by phagocytosis. NADPH oxidase contributes to neutrophil apoptosis, the formation of neutrophil extracellular traps (NETs), and converts molecules of oxygen to superoxide anions [ 142 ]. Extracellular superoxide and nitric oxide form peroxynitrite, which is involved in the killing of the parasite, but it also leads to cytotoxicity by direct peroxidation of lipids in cell membranes or the formation of reactive hydroxyl radical and nitrogen dioxide [ 143 , 144 ].…”