The NADPH oxidase DUOX1 is prominently expressed within the respiratory epithelium and has been invoked in innate airway epithelial responses to injury or infectious stimuli, by promoting H2O2-dependent signaling pathways that mediate wound responses and production of various inflammatory mediators or mucin genes. In studies during the previous funding cycle, we have identified oxidative mechanisms by which DUOX1 activation promotes the activation of epidermal growth factor receptor (EGFR) as a critical event in wound responses and inflammatory mediator production, and observed increased DUOX1 expression in models of allergic asthma in association with increased EGFR activation and mucus metaplasia. The respiratory epithelium is critical in coordinating innate and adaptive immune responses to airborne allergens, by production of epithelial cytokines such as interleukin-33 (IL-33). IL-33 was recently identified as a critical mediator in animal models of allergic inflammation, and a major susceptibility gene for asthma. IL-33 is normally present within the nuclei of pulmonary epithelial cells, and is rapidly secreted in response to various stimuli and allergens to function as an alarmin that stimulates ST2 receptors on target cells to induce innate TH2 cell-dominant immune responses. The cellular mechanisms involved in regulating IL-33 secretion are still poorly understood, however, and we now present preliminary evidence demonstrating the importance of DUOX1-dependent production of H2O2 as a critical mediator in epithelial IL-33 secretion in response to two common allergens, Alternaria alternata and Dermatophagoides pteronyssinus (house dust mite). Our studies further indicate the importance of protease-activated receptors (PAR) and transient receptor potential (TRP) channels in proximal responses to these allergens leading to DUOX1 activation and IL-33 secretion. In addition, we have preliminary evidence demonstrating H2O2-mediated EGFR activation as a critical mechanism by which DUOX1 activation promotes nuclear export and/or secretion of IL-33. The main objectives of this renewal application are to establish the common role of DUOX1 activation in mediating IL-33 secretion and subsequent allergic inflammation by various protease allergens (Aim 1), to clarify the downstream redox mechanisms by which DUOX1 activation promotes IL-33 nuclear export and secretion, focusing on the role of EGFR activation (Aim 2), and to expand our findings in studies with human subjects with allergic asthma by determining associations between DUOX1 expression and activation in nasal epithelial allergen responses in these patients (Aim 3). Successful accomplishment of these studies would identify DUOX1 as a novel and attractive therapeutic target in the management of asthma and/or its exacerbations.

Public Health Relevance

The respiratory epithelium contains the NADPH oxidase DUOX1, which produces the oxidant H2O2 in response to injury or environmental or infectious stimuli, and we have recently demonstrated that DUOX1-dependent H2O2 contributes importantly to innate airway epithelial wound responses and helps maintain airway epithelial integrity. In addition, we have also found that DUOX1 can be activated by common airborne asthma-inducing allergens, such as molds or house dust mite, and that airway DUOX1 expression is increased in models of allergic asthma, which suggests that elevated activation of DUOX1 may be important in asthma development. We now show that one of the main consequences of allergen-induced DUOX1 activation is the airway epithelial secretion of the cytokine IL-33, which is known to contribute to inducing TH2 cell-dominant allergic inflammation. In the present renewal application, we wish to establish the initial mechanisms by which diverse asthma-inducing allergens result in DUOX1 activation, and whether DUOX1 is critical in epithelial IL-33 secretion and subsequent allergic inflammation. Secondly, we wish to clarify the cellular mechanisms by which DUOX1-derived H2O2 production promotes IL-33 secretion. Finally, we wish to expand these findings in studies with human subjects with allergic asthma, to determine whether alterations in DUOX1 expression are associated with activation in nasal epithelial allergen responses in these patients. If successful, our studies would identify DUOX1 as a novel and attractive therapeutic target in the management of asthma and/or its exacerbations.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL085646-06
Application #
8704447
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Noel, Patricia
Project Start
2006-07-01
Project End
2017-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
6
Fiscal Year
2014
Total Cost
$384,834
Indirect Cost
$132,484
Name
University of Vermont & St Agric College
Department
Pathology
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
Heppner, David E; Hristova, Milena; Dustin, Christopher M et al. (2016) The NADPH Oxidases DUOX1 and NOX2 Play Distinct Roles in Redox Regulation of Epidermal Growth Factor Receptor Signaling. J Biol Chem 291:23282-23293
Habibovic, Aida; Hristova, Milena; Heppner, David E et al. (2016) DUOX1 mediates persistent epithelial EGFR activation, mucous cell metaplasia, and airway remodeling during allergic asthma. JCI Insight 1:e88811
Danyal, Karamatullah; de Jong, Willem; O'Brien, Edmund et al. (2016) Acrolein and thiol-reactive electrophiles suppress allergen-induced innate airway epithelial responses by inhibition of DUOX1 and EGFR. Am J Physiol Lung Cell Mol Physiol 311:L913-L923
Heppner, David E; van der Vliet, Albert (2016) Redox-dependent regulation of epidermal growth factor receptor signaling. Redox Biol 8:24-7
Hoffman, Sidra M; Qian, Xi; Nolin, James D et al. (2016) Ablation of Glutaredoxin-1 Modulates House Dust Mite-Induced Allergic Airways Disease in Mice. Am J Respir Cell Mol Biol 55:377-86
Little, A C; Sham, D; Hristova, M et al. (2016) DUOX1 silencing in lung cancer promotes EMT, cancer stem cell characteristics and invasive properties. Oncogenesis 5:e261
Jones, Jane T; Qian, Xi; van der Velden, Jos L J et al. (2016) Glutathione S-transferase pi modulates NF-κB activation and pro-inflammatory responses in lung epithelial cells. Redox Biol 8:375-82
McMillan, David H; van der Velden, Jos L J; Lahue, Karolyn G et al. (2016) Attenuation of lung fibrosis in mice with a clinically relevant inhibitor of glutathione-S-transferase π. JCI Insight 1:
O'Brien, Edmund; Spiess, Page C; Habibovic, Aida et al. (2016) Inhalation of the reactive aldehyde acrolein promotes antigen sensitization to ovalbumin and enhances neutrophilic inflammation. J Immunotoxicol 13:191-7
Hristova, Milena; Habibovic, Aida; Veith, Carmen et al. (2016) Airway epithelial dual oxidase 1 mediates allergen-induced IL-33 secretion and activation of type 2 immune responses. J Allergy Clin Immunol 137:1545-1556.e11

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