Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form
D-Scholarship @ Pitt Banner and Links to Homepage

NADPH oxidase limits innate immune responses in the lungs in mice

Segal, BH and Han, W and Bushey, JJ and Joo, M and Bhatti, Z and Feminella, J and Dennis, CG and Vethanayagam, RR and Yull, FE and Capitano, M and Wallace, PK and Minderman, H and Christman, JW and Sporn, MB and Chan, J and Vinh, DC and Holland, SM and Romani, LR and Gaffen, SL and Freeman, ML and Blackwell, TS (2010) NADPH oxidase limits innate immune responses in the lungs in mice. PLoS ONE, 5 (3).

[img]
Preview
 PDF
Published Version
Available under License : See the attached license file.
Download (4MB) | Preview
[img] Plain Text (licence)
Available under License : See the attached license file.
Download (1kB)

Abstract

Background: Chronic 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 Findings: We 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-kB 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-kB activation. Conclusions/Significance: These 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.

Share

Citation/Export:
Social Networking:
Share |

Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Segal, BH
Han, W
Bushey, JJ
Joo, M
Bhatti, Z
Feminella, J
Dennis, CG
Vethanayagam, RR
Yull, FE
Capitano, M
Wallace, PK
Minderman, H
Christman, JW
Sporn, MB
Chan, J
Vinh, DC
Holland, SM
Romani, LR
Gaffen, SLsarah.gaffen@pitt.eduSIG65
Freeman, ML
Blackwell, TS
Date: 1 December 2010
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 5
Number: 3
DOI or Unique Handle: 10.1371/journal.pone.0009631
Refereed: Yes
MeSH Headings: Animals; Cytokines--metabolism; Gene Expression Regulation, Enzymologic; Granulomatous Disease, Chronic--enzymology; Granulomatous Disease, Chronic--immunology; Immunity, Innate; Inflammation; Lung--immunology; Lung--metabolism; Macrophages--metabolism; Membrane Glycoproteins--genetics; Mice; NADPH Oxidase--genetics; NADPH Oxidase--metabolism; NF-E2-Related Factor 2--metabolism; NF-kappa B--metabolism; Oxidation-Reduction
Other ID: NLM PMC2838778
PubMed Central ID: PMC2838778
PubMed ID: 20300512
Date Deposited: 03 Aug 2012 18:58
Last Modified: 22 Jun 2021 14:55
URI: http://d-scholarship.pitt.edu/id/eprint/13339

Metrics

Monthly Views for the past 3 years

Plum Analytics

Altmetric.com

Actions (login required)

View Item View Item