NOX2-dependent regulation of inflammation

Abstract

NADPH oxidase (NOX) isoforms together have multiple functions that are important for normal physiology and have been implicated in the pathogenesis of a broad range of diseases, including atherosclerosis, cancer and neurodegenerative diseases. The phagocyte NADPH oxidase (NOX2) is critical for antimicrobial host defence. Chronic granulomatous disease (CGD) is an inherited disorder of NOX2 characterized by severe life-threatening bacterial and fungal infections and by excessive inflammation, including Crohn's-like inflammatory bowel disease (IBD). NOX2 defends against microbes through the direct antimicrobial activity of reactive oxidants and through activation of granular proteases and generation of neutrophil extracellular traps (NETs). NETosis involves the breakdown of cell membranes and extracellular release of chromatin and neutrophil granular constituents that target extracellular pathogens. Although the immediate effects of oxidant generation and NETosis are predicted to be injurious, NOX2, in several contexts, limits inflammation and injury by modulation of key signalling pathways that affect neutrophil accumulation and clearance. NOX2 also plays a role in antigen presentation and regulation of adaptive immunity. Specific NOX2-activated pathways such as nuclear factor erythroid 2-related factor 2 (Nrf2), a transcriptional factor that induces antioxidative and cytoprotective responses, may be important therapeutic targets for CGD and, more broadly, diseases associated with excessive inflammation and injury.

Keywords: NADPH oxidase; NADPH oxidase.; NOX2; host defence; immune cells; immunology; inflammation.

Figure 1. The phagocyte NADPH oxidase (NOX2) is a crucial enzyme in antimicrobial host defence and in regulating inflammation

Activation of NOX2 requires translocation of the cytoplasmic subunits p40^phox, p47^phox and p67^phox and Rac to the membrane-bound cytochrome comprised of p22^phox and gp91^phox. Molecular oxygen is converted to superoxide anion, which can be converted to downstream metabolites with antimicrobial activity, including H₂O₂ and hydroxyl anion. In neutrophils, MPO converts H₂O₂ to hypohalous acid.

Figure 2. NOX2-mediated antifungal host defence

NOX2 mediates host defence by both ROI generated by the NOX2-halide system, and downstream signalling, including autophagy in macrophages and the generation of NETs in neutrophils. Alveolar macrophages, which are the first line of phagocyte host defence against inhaled fungi, phagocytose and kill Aspergillus spores. Although spores are relatively immunologically inert, exposure of the fungal cell wall component, β-glucan, during the germling stage activates Dectin-1 and other PRR. This results in NF-κB activation, production of pro-inflammatory cytokines, and activation of NOX2. Macrophage NOX2 limits the growth of phagocytosed spores and germlings by ROI generation and through activation of autophagy. Autophagy, in addition to its host defence function, limits IL-1β. NOX2 in macrophages, and potentially in dendritic cells, can also limit Th17 expansion. Neutrophils principally target the extracellular hyphal stage. NOX2-mediated hyphal injury can occur via direct ROI injury, as well as through NET generation, in which chromatin and granular constituents are released extracellularly.