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

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 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. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

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