Role of macrophages in cockroach allergen-induced asthma

Thesis (Ph.D.)--Boston UniversityAsthma is a common chronic inflammatory disease representing a significant socio-economic burden, and the incidence is rising in both developed and developing countries. Our lab has previously developed a robustly reproducible cockroach allergen induced asthma model using outbred HSD:ICR mice which induces many of the same features as seen in other mouse models of human disease, including airway hyper-responsiveness, mucin production, and pulmonary inflammatory cell recruitment. The studies presented here focus on the role of macrophages, which are often overlooked in favor of other cell types that have more specifically identified functions in asthma. In fact, macrophages are the most prevalent immune cell type found in the lungs and are not only involved in innate barrier immune functions, but also play key roles in the development, direction, and maintenance of adaptive immune responses. There is currently a dearth of information regarding the macrophage in cockroach allergen (CRA)-induced asthma. Macrophages were found to be recruited to the lung in high numbers following CRA exposure. In addition, a distinct phenotypic difference between macrophages harvested from naïve versus exposed mice was noted, based on their surface expression levels of the co-stimulatory molecules CD80 and CD86. Ex vivo culture showed that lung cells from exposed mice produced increased amounts of the TH2 cytokines IL-4 and -13, and had impaired production of TNFα, KC, and MIP2, as compared to naïve cells. The effect was not systemic, as peritoneal macrophages did not show any changes in number or phenotype following CRA exposures. To assess the role of macrophage phenotypes in asthma pathogenesis, we developed a protocol to transfer autologous peritoneal macrophages into the lungs. This resulted in a reduction in total inflammatory cell recruitment, with significant reduction in the number of eosinophils in the BAL, and reduced eosinophil peroxidase activity in the lung. In addition, the transfer resulted in significantly reduced levels of Eotaxins in the lung. Depletion of macrophages using clodronate containing liposomes also resulted in reduced eosinophil recruitment and Eotaxin production In conclusion, the studies presented here highlight the role of macrophages in the pathogenesis of CRA-induced asthma, particularly with regard to eosinophil recruitment