The roles of NADPH oxidase in modulating neutrophil effector responses

Abstract

Neutrophils are phagocytic innate immune cells essential for killing bacteria via activation of a wide variety of effector responses and generation of large amounts of reactive oxygen species (ROS). Majority of the ROS in neutrophils is generated by activation of the superoxide-generating enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Independent of their anti-microbial function, NADPH oxidase-derived ROS have emerged as key regulators of host immune responses and neutrophilic inflammation. Data from patients with inherited defects in the NADPH oxidase subunit alleles that ablate its enzyme function as well as mouse models demonstrate profound dysregulation of host inflammatory responses, neutrophil hyper-activation and tissue damage in response to microbial ligands or tissue trauma. A large body of literature now demonstrates how oxidants function as essential signaling molecules that are essential for the regulation of neutrophil responses during priming, degranulation, neutrophil extracellular trap formation, and apoptosis, independent of their role in microbial killing. In this review we summarize how NADPH oxidase-derived oxidants modulate neutrophil function in a cell intrinsic manner and regulate host inflammatory responses. In addition, we summarize studies that have elucidated possible roles of oxidants in neutrophilic responses within the oral mucosa and periodontal disease.

Keywords: NADPH oxidase; chronic granulomatous disease; gp91phox; neutrophils; oxidative stress; periodontal disease; reactive oxygen species.

FIGURE 1

NADPH oxidase structure and assembly. The membrane-restricted heterodimer of NADPH oxidase is comprised of gp91^phox and p22^phox subunits. This heterodimer is known as flavocytochrome_b558. In an inactive state, the cytosolic subunits p67^phox, p47^phox, and p40^phox remain in the cytosol in a self-inhibitory confirmation. On activation, cellular kinases induce the phosphorylation of cytosolic subunits, releasing the inhibitory confirmation. p67^phox, p47^phox, and p40^phox translocate to the membrane along with Rac-GTP and bind to the flavocytochrome_b558 forming an active enzyme complex. NADPH-derived electrons are transferred to the substrate molecular oxygen (O₂) generating superoxide (O₂⁻) on the other side of the membrane.

FIGURE 2

NADPH oxidase derived ROS differentially modulate neutrophil effector responses. NADPH oxidase deficient (oxidase null) neutrophils are deficient in killing of catalase positive microorganisms and Aspergillus species. NET production is also compromised in response to select stimuli. ROS deficiency enhances degranulation, cytokine and chemokine generation that might lead to persistent inflammation by recruitment of other immune cells and/or their differential polarization. NADPH, nicotinamide adenine dinucleotide phosphate; NET, neutrophil extracellular traps; ROS, reactive oxygen species