Abstract
BackgroundChronic granulomatous disease (CGD), an inherited disorder of the NADPH oxidase in which phagocytes are defective in generating superoxide anion and downstream reactive oxidant intermediates (ROIs), is characterized by recurrent bacterial and fungal infections and by excessive inflammation (e.g., inflammatory bowel disease). The mechanisms by which NADPH oxidase regulates inflammation are not well understood.Methodology/Principal FindingsWe found that NADPH oxidase restrains inflammation by modulating redox-sensitive innate immune pathways. When challenged with either intratracheal zymosan or LPS, NADPH oxidase-deficient p47phox−/− mice and gp91phox-deficient mice developed exaggerated and progressive lung inflammation, augmented NF-κB activation, and elevated downstream pro-inflammatory cytokines (TNF-α, IL-17, and G-CSF) compared to wildtype mice. Replacement of functional NADPH oxidase in bone marrow-derived cells restored the normal lung inflammatory response. Studies in vivo and in isolated macrophages demonstrated that in the absence of functional NADPH oxidase, zymosan failed to activate Nrf2, a key redox-sensitive anti-inflammatory regulator. The triterpenoid, CDDO-Im, activated Nrf2 independently of NADPH oxidase and reduced zymosan-induced lung inflammation in CGD mice. Consistent with these findings, zymosan-treated peripheral blood mononuclear cells from X-linked CGD patients showed impaired Nrf2 activity and increased NF-κB activation.Conclusions/SignificanceThese studies support a model in which NADPH oxidase-dependent, redox-mediated signaling is critical for termination of lung inflammation and suggest new potential therapeutic targets for CGD.
Highlights
The lung is an interface where inhaled microbes and antigens interact with host defense cells
We evaluated whether NADPH oxidase activity would counterbalance the immediate pro-inflammatory events that follow Pathogen recognition receptors (PRRs) signaling by interacting with redox-sensitive pathways to dampen inflammation
We asked whether NADPH oxidase, which is activated by bacterial and fungal pathogens, would have a role in restraining lung inflammation induced by microbial motifs
Summary
The lung is an interface where inhaled microbes and antigens interact with host defense cells. Consistent with these in vivo findings, zymosan treatment resulted in increased NF-kB activation in isolated p47phox2/2 bone marrow-derived macrophages (BMDMs) compared to WT Since it is possible that p47phox can modulate inflammation independently of NADPH oxidase, we evaluated zymosan-induced lung inflammation in X-linked gp91phox2/ CGD mice [21].
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.