Hyperinflammation in chronic granulomatous disease and anti-inflammatory role of the phagocyte NADPH oxidase

Abstract

Chronic granulomatous disease (CGD) is an immunodeficiency caused by the lack of the superoxide-producing phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. However, CGD patients not only suffer from recurrent infections, but also present with inflammatory, non-infectious conditions. Among the latter, granulomas figure prominently, which gave the name to the disease, and colitis, which is frequent and leads to a substantial morbidity. In this paper, we systematically review the inflammatory lesions in different organs of CGD patients and compare them to observations in CGD mouse models. In addition to the more classical inflammatory lesions, CGD patients and their relatives have increased frequency of autoimmune diseases, and CGD mice are arthritis-prone. Possible mechanisms involved in CGD hyperinflammation include decreased degradation of phagocytosed material, redox-dependent termination of proinflammatory mediators and/or signaling, as well as redox-dependent cross-talk between phagocytes and lymphocytes (e.g. defective tryptophan catabolism). As a conclusion from this review, we propose the existence of ROS high and ROS low inflammatory responses, which are triggered as a function of the level of reactive oxygen species and have specific characteristics in terms of physiology and pathophysiology.

Lupus-associated causal mutation in neutrophil cytosolic factor 2 (NCF2) brings unique insights to the structure and function of NADPH oxidase

“…Our results corroborate more recent findings suggesting that ROS produced by the NOX2 complex are used in fine-tuning inflammatory responses, depending on when, where, and at what level the ROS are produced (29,30). A point mutation in NCF1 results in decreased ROS production (comparable to those seen in our H389Q experiments), leading to increased susceptibility to autoimmune arthritis in rodents (31,32).…”

Reactive oxygen species–independent activation of the IL-1β inflammasome in cells from patients with chronic granulomatous disease

“…In addition to these arguments, it should be kept in mind that the concept that ROS induces inflammasome activation is at odds with the known proinflammatory phenotype of patients with CGD, characterized by the occurrence of sterile granulomas, colitis, and inflammatory skin and urogenital reactions, in which IL-1β is thought to play an important pathogenic role (15). In contrast, our findings of the inhibitory effects of ROS on caspase-1 activation agree with a proinflammatory state in CGD, because we found that the release of mature IL-1β was normal and after certain stimuli even increased in cells of CGD patients.…”

“…On the one hand, ROS have been suggested to induce NF-κB activation (12,13), and several in vitro studies have proposed that activation of the inflammasome is strictly dependent on ROS generation (11,14). On the other hand, other studies have reported anti-inflammatory effects of the NADPH system and ROS (15), and a recent study in mice defective for the generation of ROS strongly suggested anti-inflammatory effects of oxygen species (16). In line with this, patients with chronic granulomatous diseases (CGDs) with defects in the NADPH system and, consequently, defective ROS generation (17) display an inflammatory phenotype characterized by granulomas and Crohn-like colitis (18).…”

NADPH oxidase controls neutrophilic response to sterile inflammation in mice by regulating the IL-1α/G-CSF axis

“…A distinctive component of CGD is its association with inflammatory conditions, often unrelated to infection, including granulomatous inflammation in the gastrointestinal and genitourinary tracts, discoid lupus-like lesions, and macrophage activation syndrome. [2][3][4][5][6] Moreover, NADPH oxidase gene variants are linked to lupus, rheumatoid arthritis, and inflammatory bowel disease. [7][8][9][10] However, insights into the role of NADPH oxidase in regulating inflammatory responses to sterile endogenous ligands are lacking, an important question given the association of NADPH oxidase deficiency with noninfectious inflammatory disorders.…”