Mast cells and their progenitors in respiratory diseases : Understanding their connection to lung function and airway inflammation

Sammanfattning: Mast cells are rare immune cells involved in allergic diseases, including asthma. These cells are derived from mast cell progenitors (MCps) that migrate to the peripheral tissues via the blood in response to allergic or non-allergic stimuli. The main purpose of this thesis was to investigate the role of mast cells and MCps in the lung function decline observed in mouse models of airway inflammation. We also investigated the MCp frequency during natural allergen exposure using patient samples. Our aim in paper I was to investigate the effect of age and weight on lung function parameters in naïve mice using a pulmonary function test (PFT). We showed that age and weight positively correlated with lung function and successfully used the PFT to monitor asthma outcomes and distinguish between treated and untreated experimental asthma.In paper II, we investigated the specificity of a basophil-deficient mouse model that relies on the deletion of the mast cell protease 8 (mMCP-8), a classical basophil marker. We found that lung mast cells expressed mMCP-8, and deleting this protease reduced lung mast cells in mice with allergic airway inflammation.Mast cells express ST2 and thus can be activated by interleukin-33 (IL-33). Hence, in paper III, we used Cpa3cre/+ mast cell-deficient mice to investigate the role of mast cells in airway inflammation induced by intranasal IL-33 administration. We identified a new mechanism in which mast cells participate in T-cells mobilization into the alveolar space via the CXCL1/CXCR2 axis. We have previously described increased circulating MCps in subjects with reduced lung function. However, if and how MCps change upon allergen exposure is unknown. Therefore, in paper IV, we investigated the frequency of blood MCps in birch pollen-sensitized asthma patients in and out of the birch pollen season. We demonstrated that in allergic asthma patients, circulating MCps were increased during natural pollen exposure and were associated with more asthma symptoms and less asthma control.This thesis involves both basic and translational research and provides new insights into the role of mast cells and their progenitors in type 2 inflammation.