Role of the Leukotriene E4 Receptor GPR99 in Asthma

We previously demonstrated that inhalation of common aeroallergens such as the house dust mite Dermatophagoides pteronyssinus and the mold Alternaria alternata elicits the generation of a potent proinflammatory lipid mediator, leukotriene E4 (LTE4), which is part of the cysteinyl leukotriene (CysLT) family. LTE4 promotes lung inflammation, epithelial remodeling, and release of mucus into the airway through its action on a G protein-coupled receptor called CysLT3R or GPR99 or OXGR1. During this funding period,1. We discovered that GPR99 is expressed on alpha smooth muscle actin-positive myoepithelial cells in the airway submucosa. GPR99 activation promotes myoepithelial cells to migrate to the surface of regenerating epithelium and make more brush cells. This is a feed forward loop which promotes airway remodeling. 2. We discovered that mast cell (MC) generation of LTE4 is an adjuvant signal for the development of Th1 and Th17 immunity in part through the expansion and activation of lung-draining lymph node T cells during sensitization. This likely occurs viaCysLT1 action on T cells.