The NADPH oxidase DUOX1 is prominently expressed within the respiratory epithelium and contributes to innate response mechanisms to injury or other environmental triggers, by generating reactive oxygen species (ROS) and activating redox-dependent signaling pathways. In the present funding cycle of this project, we identified DUOX1 as a critical mediator of innate epithelial responses to allergens, by promoting epithelial secretion of the alarmin IL-33 and subsequent activation of type 2 inflammation. We also observed enhanced epithelial DUOX1 in subjects with allergic asthma, and a critical role for DUOX1 in development of various critical features of house dust mite (HDM)-induced allergic airway inflammation in mice, such as mucus metaplasia, subepithelial fibrosis, and airway hyperresponsiveness. These actions of DUOX1 were largely related to redox-dependent activation of Src family kinases and epidermal growth factor receptor (EGFR) signaling, both well-recognized factors in allergic inflammation and airway remodeling, in part by mediating cysteine oxidation within these kinases. During these studies, we noted that DUOX1 is not only operative within the airway epithelium, but is also present in non- epithelial cell types such as alveolar macrophages, and appears to be involved in macrophage polarization and IL-33-mediated pro-fibrotic mediators such as IL-13 and TGF-? that are involved in airway remodeling.
The first aim of this renewal application is to delineate the cell-specific actions of DUOX1 on various aspects of HDM- induced allergic inflammation and remodeling, specifically focusing on a potential role for DUOX1 in alternative neutrophil (N2) polarization or macrophage (M2) activation.
Aim 2 is to identify redox-sensitive targets of DUOX1 and characterize the molecular mechanisms by DUOX1-dependent cysteine oxidation regulates the enzymatic function of Src, using molecular dynamics simulations and experimental studies with various cysteine variants. Finally, based on previous findings that thiol-reactive electrophiles can inhibit DUOX1 activation, aim 3 will be to develop peptide-based cysteine-targeted approaches to pharmacologically inhibit DUOX1 activity, thus filling an unmet need for DUOX1-selective inhibitors that may be used for clinical development in treatment of severe asthma.
This renewal application will extend ongoing studies towards the role of the NADPH oxidase homolog DUOX1 within the respiratory epithelium. In the previous funding cycle, we discovered that DUOX1 plays a critical role in innate airway responses to airborne allergens, and contributes to various important features of allergic asthma. This renewal application seeks to further understand the molecular mechanisms by which DUOX1 controls these processes, and to develop pharmacological approaches to selectively inhibit DUOX1 for potential clinical development in treatment of severe asthma.
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| Heppner, David E; Hristova, Milena; Ida, Tomoaki et al. (2018) Cysteine perthiosulfenic acid (Cys-SSOH): A novel intermediate in thiol-based redox signaling? Redox Biol 14:379-385 |
| Anathy, Vikas; Lahue, Karolyn G; Chapman, David G et al. (2018) Reducing protein oxidation reverses lung fibrosis. Nat Med 24:1128-1135 |
| Heppner, David E; Dustin, Christopher M; Liao, Chenyi et al. (2018) Direct cysteine sulfenylation drives activation of the Src kinase. Nat Commun 9:4522 |
| van der Vliet, Albert; Janssen-Heininger, Yvonne M W; Anathy, Vikas (2018) Oxidative stress in chronic lung disease: From mitochondrial dysfunction to dysregulated redox signaling. Mol Aspects Med 63:59-69 |
| van der Vliet, Albert; Danyal, Karamatullah; Heppner, David E (2018) Dual oxidase: a novel therapeutic target in allergic disease. Br J Pharmacol 175:1401-1418 |
| Little, Andrew C; Sulovari, Arvis; Danyal, Karamatullah et al. (2017) Paradoxical roles of dual oxidases in cancer biology. Free Radic Biol Med 110:117-132 |
| Hoyt, Laura R; Randall, Matthew J; Ather, Jennifer L et al. (2017) Mitochondrial ROS induced by chronic ethanol exposure promote hyper-activation of the NLRP3 inflammasome. Redox Biol 12:883-896 |
| Heppner, David E; Janssen-Heininger, Yvonne M W; van der Vliet, Albert (2017) The role of sulfenic acids in cellular redox signaling: Reconciling chemical kinetics and molecular detection strategies. Arch Biochem Biophys 616:40-46 |
| Lundblad, Lennart K A; Gülec, Nazey; Poynter, Matthew E et al. (2017) The role of iNKT cells on the phenotypes of allergic airways in a mouse model. Pulm Pharmacol Ther 45:80-89 |
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