LAUSR

The NOX2 NADPH oxidase generates superoxide following activation by microbial or other inflammatory stimuli. Inactivating mutations in this leukocyte enzyme result in chronic granulomatous disease (CGD), a primary immunodeficiency associated with recurrent bacterial and fungal infections as well as inflammatory disorders, including inflammatory bowel disease and discoid lupus. These symptoms reflect a dual importance of the NADPH oxidase both for microbial killing and for attenuating inflammation by still incompletely understood mechanisms. Moreover, hypomorphic NADPH oxidase gene variants are linked to inflammatory bowel disease and autoimmunity. A long-term goal is to better understand how the NADPH oxidase functions as a critical host effector in these different settings. Our recent work in murine CGD suggest that excessive IL-1α released by sentinel macrophages drive hyper-inflammation in sterile peritoneal inflammation (Bagaitkar et al., Blood 2017). To further interrogate the relative role of the NADPH oxidase in different myeloid cells, we developed mice with lineage–restricted impairment of NADPH oxidase activity using Cre recombinases. Ongoing studies are investigating the impact during sterile inflammation and the response to Aspergillus, an important pathogen in CGD.