Allergens are the most common cause of acute asthma exacerbations, leading to inflammation and constriction of airway smooth muscle cells. Allergens trigger the release of interleukin(IL)-33 from various cell types in the lung. IL-33 stimulates both type 2 innate lymphoid cells (ILC2s) and T-helper 2 (Th2) cells to secrete large amounts of IL-5 and IL-13, which are important mediators of the Th2 inflammatory response. IL-5 and IL-13, along with IL-4, are responsible for the classic pathology associated with asthma: airway hyper-responsiveness, eosinophilic inflammation, and mucus hyper-secretion. Notably, these pathological findings are not present in mice lacking the receptor for advanced glycation end products (RAGE) in the house dust mite (HDM) or ovalbumin (OVA) models of asthma/allergic airway inflammation(AAI). These data suggest that RAGE, a pro- inflammatory, multi-ligand, immunoglobulin-like receptor that is highly expressed in the lung, is necessary for the development of an allergen-induced asthmatic Th2 response. Both RAGE knockout (KO) and wild-type (WT) mice demonstrate normal increases in IL-4, immunoglobulin(Ig)-G, and IgE in response to HDM or OVA, however, only WT mice demonstrate increases in cytokines IL-5 and IL-13. The inability to mount an IL-5 and IL-13 response after allergen exposure in the absence of RAGE could be due to defects in the adaptive immune system (Th2 cells), the innate immune system (ILC2s), or both. Furthermore, these deficits in Th2 cytokine production may be secondary to an inability of RAGE KO mice to increase levels of IL-33, which was also abnormally not increased in RAGE KO mice as compared to WT mice treated with HDM. This investigation seeks to study the upstream signaling events that control the induction of the Th2 response following allergen exposure. First, flow cytometry will be use to determine if absence of RAGE signaling impairs cellular recruitment and/or cytokine production in Th2 cells, ILC2s, or both. Next, cell culture studies will determine if RAGE signaling increases IL-5 and IL-13 production indirectly by promoting IL-33 secretion and/or through direct RAGE signaling on Th2 cells, ILC2s, or both. Understanding the mechanisms by which loss of RAGE signaling prevents asthma pathogenesis may lead to the discovery of new therapeutic targets for the treatment of asthma or the prevention of allergen-induced exacerbations of the disease.
Asthma is one of the leading causes of morbidity worldwide, and exacerbations of the disease, leading to bronchoconstriction and difficulty breathing, are commonly triggered by environmental particulates such as allergens. This project aims to understand the mechanism by which the receptor for advanced glycation end products (RAGE) promotes inflammation and airway hyper-responsiveness in allergen-induced asthma. Understanding this molecular process may lead to novel therapeutics that (1) prevent asthma exacerbations or disease development, or (2) help to treat patients whose asthma does not respond to current bronchodilator or corticosteroid therapies.
|Oczypok, Elizabeth A; Perkins, Timothy N; Oury, Tim D (2017) All the ""RAGE"" in lung disease: The receptor for advanced glycation endproducts (RAGE) is a major mediator of pulmonary inflammatory responses. Paediatr Respir Rev 23:40-49|
|Oczypok, Elizabeth A; Perkins, Timothy N; Oury, Tim D (2017) Alveolar Epithelial Cell-Derived Mediators: Potential Direct Regulators of Large Airway and Vascular Responses. Am J Respir Cell Mol Biol 56:694-699|
|Oczypok, Elizabeth A; Milutinovic, Pavle S; Alcorn, John F et al. (2015) Pulmonary receptor for advanced glycation end-products promotes asthma pathogenesis through IL-33 and accumulation of group 2 innate lymphoid cells. J Allergy Clin Immunol 136:747-756.e4|
|Oczypok, Elizabeth A; Oury, Tim D (2015) Electron microscopy remains the gold standard for the diagnosis of epithelial malignant mesothelioma: a case study. Ultrastruct Pathol 39:153-8|
|Gregory, Alyssa D; Kliment, Corrine R; Metz, Heather E et al. (2015) Neutrophil elastase promotes myofibroblast differentiation in lung fibrosis. J Leukoc Biol 98:143-52|