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Leukotriene E4 elicits respiratory epithelial cell mucin release through the G-protein–coupled receptor, GPR99

Significance Leukotriene E4 (LTE4), a lipid mediator detected in asthma exacerbations triggered by allergen, viruses, and aspirin, elicits airflow obstruction and lung inflammation in asthmatics. GPR99 is the recently identified high-affinity receptor for LTE4 and is resistant to blockade by commercially available cysteinyl leukotriene (cysLT) receptor antagonists. Here we find that GPR99 is expressed in respiratory epithelial cells and mediates mucin release and submucosal swelling in response to LTE4 or to cysLTs elicited by Alternaria, a common airborne fungus. Furthermore, among cysLT receptors, only GPR99 regulates baseline numbers of mucin-containing goblet cells. These studies demonstrate a unique role for GPR99 in epithelial cell homeostasis and activation and indicate that epithelial cells may be a dominant site of LTE4 action in the lung. Cysteinyl leukotrienes (cysLTs), leukotriene C4 (LTC4), LTD4, and LTE4 are proinflammatory lipid mediators with pathobiologic function in asthma. LTE4, the stable cysLT, is a weak agonist for the type 1 and type 2 cysLT receptors (CysLTRs), which constrict airway smooth muscle, but elicits airflow obstruction and pulmonary inflammation in patients with asthma. We recently identified GPR99 as a high-affinity receptor for LTE4 that mediates cutaneous vascular permeability. Here we demonstrate that a single intranasal exposure to extract from the respiratory pathogen Alternaria alternata elicits profound epithelial cell (EpC) mucin release and submucosal swelling in the nasal mucosa of mice that depends on cysLTs, as it is absent in mice deficient in the terminal enzyme for cysLT biosynthesis, LTC4 synthase (LTC4S). These mucosal changes are associated with mast cell (MC) activation and absent in MC-deficient mice, suggesting a role for MCs in control of EpC function. Of the three CysLTRs, only GPR99-deficient mice are fully protected from EpC mucin release and swelling elicited by Alternaria or by intranasal LTE4. GPR99 expression is detected on lung and nasal EpCs, which release mucin to doses of LTE4 one log lower than that required to elicit submucosal swelling. Finally, mice deficient in MCs, LTC4S, or GPR99 have reduced baseline numbers of goblet cells, indicating an additional function in regulating EpC homeostasis. These results demonstrate a novel role for GPR99 among CysLTRs in control of respiratory EpC function and suggest that inhibition of LTE4 and of GPR99 may have therapeutic benefits in asthma.