Oral mucosal complications in chronic granulomatous disease - a role of Nox2 oxidase in regulating oral neutrophil responses

Abstract Chronic granulomatous disease (CGD) is a devastating immunodeficiency caused by inactivating mutations in the superoxide-generating leukocyte NADPH oxidase 2 (NOX2). Patients with CGD suffer from recurrent life-threatening infections and a dysregulated inflammatory response. Significant oral complications such as recurrent oral ulcerations, stomatitis, and gingivitis cause considerable morbidity in CGD. However, the underlying molecular and cellular drivers remain incompletely understood. Using a preclinical murine model of CGD, we found that inducing oral mucosal inflammation in Cybb/Nox2 knockout (CybbKO) mice resulted in microbial dysbiosis and significant ulceration of oral soft tissues, and inflammatory destruction of the alveolar bone compared to wild-type (WT) mice. Oral inflammation in CybbKOdid not result in systemic dissemination of oral microbes or defective antimicrobial clearance. Instead, transcriptional and cellular profiling identified a predominant neutrophilic signature accompanied by elevated levels of neutrophil mobilizing and recruiting factors, proinflammatory cytokines, and a depressed activation of genes regulated by the Nuclear factor erythroid 2-related factor 2 (Nrf2) genes. Nox2-deficient neutrophils effectively cleared oral periodontal pathogens but exhibited excessive degranulation and produced significantly higher inflammatory and tissue-degrading mediators, indicating a dysregulated cell-intrinsic response in the absence of Nox2 activity. The use of Nrf2 synthetic agonists partially ameliorated oral damage in CybbKO mice by preventing excessive neutrophilic inflammation. Thus, our studies demonstrate that Nox2 oxidase and derivative reactive oxygen species are essential for balanced recruitment and cell-intrinsic regulation of neutrophil effector and inflammatory responses within oral tissues. Furthermore, our studies provide the first insights into the drivers of oral complications in CGD patients.