Nadph Oxidase Limits Sterile Inflammation By Modulating Il-1/G-Csf-Driven Neutrophilic Inflammation

The phagocyte NADPH oxidase is a multi-subunit enzyme that generates superoxide in response to multiple agonists. Besides their role in microbial killing, NADPH oxidase-derived reactive oxygen species (ROS) are important in regulating inflammation and have emerging links to autoimmunity. Patients with chronic granulomatous disease (CGD) have null mutations in NADPH oxidase subunit genes and absent enzyme activity, presenting not only with recurrent bacterial and fungal infections but also inflammatory conditions and an association with autoimmune disorders. How the NADPH oxidase regulates inflammatory processes independent of its role in microbial infection is incompletely characterized. We hypothesized that NADPH oxidase deficiency influences the magnitude of inflammatory mediators released in response to Danger Associated Molecular Patterns (DAMPs) during the acute phase of sterile tissue injury. Of note, prior studies (Chen et al Nature Medicine 2007; Kono et al, J Immunol 2010) identified IL-1α released by sentinel macrophages as a key mediator of the initial response to sterile cell death.