The Active Barrier: A Role for Epithelial Cells in Chitin Induced Allergic Inflammation

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The Active Barrier: A Role for Epithelial Cells in Chitin Induced Allergic Inflammation


Roy, Rene M.



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Chitin is a linear polysaccharide of N-acetylglucosamine that is absent in vertebrates but that forms the cell wall of fungi, the exoskeleton of insects, and the shell of crustaceans. Exposure to chitin and chitin-associated environmental allergens is associated with an increase in allergic disease and asthma yet little is known about how chitin is recognized by the immune system or the mechanism by which chitin can promote allergic disease. Previous studies have focused on the interaction of chitin with the macrophage to explore the immunological impact of chitin and have yielded conflicting results, namely that macrophages become alternatively activated in vivo but classically activated in vitro following chitin exposure. I hypothesized that, in vivo, chitin promoted the alternative activation of macrophages and allergic inflammation via interaction with another cell.Airway epithelial cells represent the first point of contact for inhaled particles and are important mediators of allergic airway disease. This dissertation investigates the role of airway epithelial cells in mediating allergic inflammation following chitin exposure. Airway epithelial cells bind chitin and secrete CCL2 in vitro and in vivo. CCL2 is required for chitin induced alternative activation of macrophages in vitro and the CCL2 receptor--CCR2--is required for innate allergic inflammation in vivo.Chitin also promotes adaptive allergic inflammation in a model of chitin-dependent sensitization to Aspergillus antigens. Chitin-dependent sensitization to Aspergillus antigens requires complement factor 3 and the anaphylatoxin receptor C3aR. In addition, chitin-dependent activation of airway epithelial cell NF-kB is required for the polarization of Aspergillus -specific T cells toward allergy associated Th2 and severe allergy associated Th17 phenotypes. Also, chitin-dependent sensitization to Aspergillus antigens results in pulmonary eosinophilia and elevated levels of IgE. Both eosinophilia and elevated IgE are dependent on the C3-C3aR axis and airway epithelial cell NF-kB activation.Thus, chitin exposure activates airway epithelial cells to promote innate and adaptive allergic inflammation. The interaction of airway epithelial cells with chitin could represent an early event in the development of allergic airway disease and asthma.