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 #
2R01HL085646-05A1
Application #
8598274
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
2013-08-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2013
Total Cost
$373,839
Indirect Cost
$128,699
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
van der Vliet, Albert; Janssen-Heininger, Yvonne M W (2014) Hydrogen peroxide as a damage signal in tissue injury and inflammation: murderer, mediator, or messenger? J Cell Biochem 115:427-35
Sham, Derek; Wesley, Umadevi V; Hristova, Milena et al. (2013) ATP-mediated transactivation of the epidermal growth factor receptor in airway epithelial cells involves DUOX1-dependent oxidation of Src and ADAM17. PLoS One 8:e54391
Janssen-Heininger, Yvonne M W; Nolin, James D; Hoffman, Sidra M et al. (2013) Emerging mechanisms of glutathione-dependent chemistry in biology and disease. J Cell Biochem 114:1962-8
Randall, Matthew J; Hristova, Milena; van der Vliet, Albert (2013) Protein alkylation by the *,*-unsaturated aldehyde acrolein. A reversible mechanism of electrophile signaling? FEBS Lett 587:3808-14
Gorissen, Stefan H; Hristova, Milena; Habibovic, Aida et al. (2013) Dual oxidase-1 is required for airway epithelial cell migration and bronchiolar reepithelialization after injury. Am J Respir Cell Mol Biol 48:337-45
Hristova, Milena; Spiess, Page C; Kasahara, David I et al. (2012) The tobacco smoke component, acrolein, suppresses innate macrophage responses by direct alkylation of c-Jun N-terminal kinase. Am J Respir Cell Mol Biol 46:23-33
Bovill, Edwin G; van der Vliet, Albert (2011) Venous valvular stasis-associated hypoxia and thrombosis: what is the link? Annu Rev Physiol 73:527-45
Paveglio, Sara A; Allard, Jenna; Foster Hodgkins, Samantha R et al. (2011) Airway epithelial indoleamine 2,3-dioxygenase inhibits CD4+ T cells during Aspergillus fumigatus antigen exposure. Am J Respir Cell Mol Biol 44:11-23
Olson, Nels; Kasahara, David I; Hristova, Milena et al. (2011) Modulation of NF-*B and hypoxia-inducible factor--1 by S-nitrosoglutathione does not alter allergic airway inflammation in mice. Am J Respir Cell Mol Biol 44:813-23
van der Vliet, Albert (2011) Nox enzymes in allergic airway inflammation. Biochim Biophys Acta 1810:1035-44

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