NRROS negatively regulates the production of reactive oxygen species in phagocytes during host defense and autoimmunity (P1339)

Abstract

Abstract Reactive oxygen species (ROS) produced by phagocytes are essential for host defense against bacterial and fungal infections. Individuals with defects in the ROS production machinery develop chronic granulomatous disease. On the other hand, ROS can cause collateral tissue damage during inflammatory processes and therefore needs to be tightly controlled. Here we describe a novel protein that limits ROS generation by phagocytes upon inflammatory stimuli. We named this protein as Negative Regulator of ROS (NRROS). NRROS is a previously uncharacterized leucine rich repeat containing protein expressed mainly in myeloid cells. NRROS controls protein expression and/or stability of NOX2 and p22phox, the membrane-bound subunits of the NADPH oxidase complex. NRROS deficient cells produce increased ROS upon inflammatory challenges. In vivo, NRROS deficient mice show higher capacity to control invading bacteria such as Escherichia coli and Listeria monocytogenes. Conversely, these mice develop severe experimental autoimmune encephalomyelitis, accompanied with significant mortality, due to oxidative tissue damage in the central nervous system. Interestingly, NRROS expression is differentially regulated by inflammatory stimuli. Tissue necrosis factor-α but not interferon-γ suppresses NRROS expression in macrophages. NRROS, thus, provides a hitherto undefined mechanism for ROS regulation; one that enables phagocytes to control invading pathogens while minimizing collateral tissue damage.