Research Project
7929632
DESCRIPTION (provided by applicant): Asthma is a chronic inflammatory disease of the mucosal barrier lining the airways that is seen increasingly in westernized countries. A long-term objective is to find novel ways of prevention and treatment of this disorder. Airway dendritic cells (DC) and epithelial cells play a crucial role in the process of allergic sensitization and in the control of Th2-mediated allergic inflammation typical of asthma. Barrier epithelial cells influence the function of DCs through release of cytokines. Recent data show that the administration of house dust mite (HDM) allergens to the airways of mice induced an increase in several DC-activating cytokines, amongst which interleukin (IL)-1[unreadable], the first cytokine ever discovered. Moreover, HDM-driven allergic inflammation did not occur in mice lacking the IL-1 receptor (IL-1R). How exactly IL-1 production and signaling is involved in causing allergic disease. Both hematopoietic and stromal cells can produce IL1[unreadable] and respond to it. The specific objective of this project is to unravel the precise contribution of the IL-1[unreadable]/IL-1R axis in mediating the crosstalk between epithelial cells and DCs during the process of allergic sensitization to inhaled allergens. In the research plan there is great emphasis on the construction of radiation chimeric mice in which either radioresistant stromal cells (including epithelial cells, fibroblasts, endothelial cells) or radiosensitive hematopoietic cells (including DCs, monocytes, polymorphonuclear cells and lymphocytes) are deficient in crucial pathways of the IL-1[unreadable]/IL-1R axis, such as the IL-1R, NALP3, ASC and caspase-1 proteins. In all these mice, the impact of stromal versus hematopoietic deficiency of the axis on salient features of asthma such as airway inflammation, secretion of mucus and bronchial hyperresponsiveness will be studied. A detailed analysis of the function of airway DCs will be performed, focusing on the antigen-uptake capacity, dynamic scanning behavior, migratory capacity and T cell polarizing capacity of DCs in the lungs. These analyses involve the use of cutting edge flow cytometry and imaging of the dynamic behavior of DCs in vital tracheal tissue using dual- photon microscopy. A better understanding of the way by which epithelial cells and DCs communicate could bring clarity in the process of allergic sensitization in asthma and could eventually unravel new therapeutic and preventive avenues for this disease. Knowledge originating from this project might also help explain interactions between epithelial cells and DC that occur in other mucosal disorders such as Crohn's disease and Ulcerative Colitis. Allergic asthma has increased significantly over the last 50 years, posing a significant burden to public health and affecting the daily life of many. This project will help unravel how individuals become allergic when exposed to house dust mite allergen.
