Leukotriene E4 Rapidly Amplifies Airway Type 2 Inflammation Through IL-25 and Endogenous Cysteinyl Leukotrienes
Tao Liu 1,2, Lora G. Bankova1,2, Nora A. Barrett1,2, Chunli Feng1, Junrui Lin1, Juying Lai1, and Joshua A. Boyce 1,2,3
1Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital
Departments of 2Medicine and 3Pediatrics, Harvard Medical School
Boston, MA 02115
Leukotriene E4 (LTE4), the stable metabolite of cysteinyl leukotrienes (cysLTs), accumulates in asthma, aspirin exacerbated respiratory disease (AERD) and chronic rhinosinusitis. Although it is the weakest direct bronchoconstrictor of the three cysLTs, LTE4 is disproportionately potent in the airways of subjects with asthma and AERD, and elicits both bronchial eosinophilia and mast cell (MC) activation when administered to asthmatic subjects by inhalation. We previously reported that LTE4 elicited expansion of IL-25-expressing tracheal brush cells (BrCs) and mild airway eosinophilia in naïve mice by a pathway requiring the type 3 cysteinyl leukotriene receptor (CysLT3R). We now report that LTE4 rapidly amplifies features of type 2 immunopathology by a pathway requiring all three cysLT receptors, and sequential actions of IL-25, IL-33, and endogenously generated LTC4. A single inhaled dose of LTE4 administered to AERD-like Ptges-/- mice elicited rapid increases in lung ILC2s, PAS+ goblet cells, and DLCK1+ brush cells in the trachea. LTE4 caused the rapid recruitment of platelet-adherent eosinophils to the lung, as well as sharp increases in airway resistance, release of mast cell activation products, and lung levels of IL-33. Deletion of CysLT3R, antibody neutralization of IL-25 and pharmacologic blockades of either CysLT1R or CysLT2R attenuated all features. Thus, LTE4 drives a potent innate type 2 response initiated by the bush cell products LTC4 and IL-25, amplified by downstream ILC2 activation, and culminates in platelet-adherent eosinophil recruitment and platelet-dependent IL-33-driven mast cell activation. These findings suggest several avenues for therapeutic development, especially in AERD where the levels of LTE4 are especially high.