NADPH OXIDASE REGULATION OF INFLAMMATION

Brahm H. Segal, MD

Author address: 

Roswell Park Cancer Institute, USA

Abstract: 

The lung is an interface where inhaled microbes and antigens interact with host defense cells. Pathogen recognition receptors such as toll-like receptors sample microbial motifs and initiate signaling that may result in NADPH oxidase activation. NADPH oxidase activation requires translocation of the cytoplasmic subunits p47phox, p67phox, and p40phox and rac to the membrane-bound flavocytochrome consisting of gp91phox and p22phox (phox, phagocyte oxidase). NADPH oxidase activation leads to generation of superoxide anion and downstream reactive oxidant intermediates (ROIs) and activation of neutrophil antimicrobial proteases. Chronic granulomatous disease (CGD) is an inherited disorder of NADPH oxidase characterized by lifethreatening bacterial and fungal infections and by abnormally exuberant inflammatory responses (e.g., inflammatory bowel disease). "œMulch pneumonitis" is a hyper-inflammatory response in CGD patients to fungal pneumonia and mouse models point to excessive inflammation in CGD resulting from intrinsic defect(s) in immune regulation. We evaluated whether NADPH oxidase activity would counterbalance the immediate pro-inflammatory events that follow PRR signaling by interacting with redox-sensitive pathways to dampen inflammation. Using p47phox-/- and gp91phox-deficient mice that lack NADPH oxidase function, we show that NADPH oxidase limits inflammation by attenuating the pro-inflammatory transcription factor NF-B and by activating Nrf2, an anti-inflammatory transcription factor. Consistent with these findings, zymosantreated PBMCs from X-linked CGD patients showed impaired Nrf2 activity and increased NF-B activation. These studies support a model in which NADPH oxidase-dependent, redox-mediated signaling is critical for termination of inflammation and suggest new potential therapeutic targets for CGD.
2010

abstract No: 

none

Full conference title: 

4th Advances Against Aspergillosis
    • AAA 4th (2010)