The cysteinyl leukotriene 3 receptor regulates expansion of IL-25–producing airway brush cells leading to type 2 inflammation

The leukotriene E4 receptor, CysLT3R, regulates allergen-elicited expansion of airway brush cells and type 2 inflammation. Brushing up on lung inflammation Inhaled environmental allergens elicit type 2 lung inflammation leading to an increase in the risk of developing allergies and asthma. Bankova et al. found that one step along this pathway depends on the lipid mediator leukotriene E4 signaling through a receptor on respiratory epithelial cells to increase the number of brush cells, a rare population of chemosensory cells in the lung epithelium that express receptors shared by taste bud cells. These brush cells were identified as the major pulmonary source for synthesis of interleukin-25 (IL-25), a proinflammatory protein increased in diseases associated with type 2 inflammation. These results highlight the contributions that leukotriene E4 and IL-25 make to the signaling pathways that perpetuate allergic diseases. Respiratory epithelial cells (EpCs) orchestrate airway mucosal inflammation in response to diverse environmental stimuli, but how distinct EpC programs are regulated remains poorly understood. Here, we report that inhalation of aeroallergens leads to expansion of airway brush cells (BrCs), specialized chemosensory EpCs and the dominant epithelial source of interleukin-25 (IL-25). BrC expansion was attenuated in mice lacking either LTC4 synthase, the biosynthetic enzyme required for cysteinyl leukotriene (CysLT) generation, or the EpC receptor for leukotriene E4 (LTE4), CysLT3R. LTE4 inhalation was sufficient to elicit CysLT3R-dependent BrC expansion in the murine airway through an IL-25–dependent but STAT6-independent signaling pathway. Last, blockade of IL-25 attenuated both aeroallergen and LTE4-elicited CysLT3R-dependent type 2 lung inflammation. These results demonstrate that CysLT3R senses the endogenously generated lipid ligand LTE4 and regulates airway BrC number and function.