Urokinase plasminogen activator receptor (uPAR) attenuates allergen-induced eosinophil migration and airway hyperresponsiveness through distinct mechanisms
Allergic asthma is a widespread disease of the airway stemming from the actions of multiple cell types, including eosinophils and epithelial cells. The urokinase plasminogen activator receptor (uPAR) is a membrane bound protein that can contribute to the activation and mobilization of leukocytes and is present at increased levels in asthmatics. However, its role in allergic asthma remains poorly understood. Here, we have used multiple mouse strains and different models of allergic asthma to study the function of uPAR in allergic airway inflammation (AHR). Plaur, the gene encoding uPAR, was rapidly induced following allergic sensitization through the airway, and again following subsequent allergen challenge. Plaur-deficient mice displayed both increased numbers of eosinophils and heightened AHR in multiple models of allergic asthma. Mice selectively lacking Plaur in eosinophils also had more robust eosinophilia than did WT mice, and eosinophils lacking Plaur displayed increased activity in an ex-vivo assay of chemokine-dependent migration. However, those mice did not have increased AHR compared with WT mice. Conversely, although mice selectively lacking Plaur in lung epithelial cells did not have increased inflammation compared with WT mice, they displayed heightened AHR. These findings suggest that uPAR controls both airway inflammation and AHR, but through distinct mechanisms. Targeting uPAR might have therapeutic potential for treating inflammation and AHR in asthma. Overall design: 8 C57B6/J (WT) mice and 8 Plaur–/– mice were sensitized on days 0 and 7 with LPS/OVA, and then subsequently challenged to aerosolized OVA on day 14.