Chronic granulomatous disease (CGD) is a rare inherited disorder of the NADPH oxidase complex in which phagocytes are defective in generating superoxide anion and downstream reactive oxidant intermediates (ROIs). CGD is characterized by recurrent life-threatening bacterial and fungal infections and by excessive inflammatory responses. Excessive inflammation in CGD is not solely the result of unresolved infection, but results from an intrinsic defect in the control of inflammation. Using genetically engineered mouse models, we have identified two possible mechanisms by which NADPH oxidase may downregulate inflammation. First, we have shown that NADPH oxidase, directly or indirectly, downregulates NF-?B activation in vitro and in vivo. Second, NADPH oxidase activates nuclear erythroid 2 p45 related factor 2 (Nrf2), a key redox-sensitive pathway with anti- inflammatory and anti-neoplastic properties. Our specific aims are focused on three inter-related questions related to how NADPH oxidase downregulates inflammation: Specific aim 1: To test the hypothesis that NADPH oxidase attenuates NF-: activation by redox-sensitive suppression of IKK2 activity. Specific aim 2: To evaluate the interaction of NADPH oxidase and Nrf2 in regulating inflammation. Specific aim 3: To test the hypothesis that NADPH oxidase-derived ROIs from neutrophils will modulate NF-??B and Nrf2 signaling in neighboring cells and reduce inflammation in CGD mice following adoptive transfer. Public Health Relevance: Chronic granulomatous disease (CGD) is a rare inherited disorder of the he NADPH oxidase, a critical component of host defense against microbial pathogens. Our proposal will evaluate mechanisms by which NADPH oxidase regulates inflammation that will be important to our understanding of CGD, and will be broadly relevant to pathologic conditions, such as inflammatory disorders and cancer.