Type 2 Cysteinyl Leukotriene Receptors Drive IL-33-Dependent Type 2 Immunopathology and Aspirin Sensitivity

J Immunol. 2018 Feb 1;200(3):915-927. doi: 10.4049/jimmunol.1700603. Epub 2017 Dec 27.


Cysteinyl leukotrienes (cysLTs) facilitate mucosal type 2 immunopathology by incompletely understood mechanisms. Aspirin-exacerbated respiratory disease, a severe asthma subtype, is characterized by exaggerated eosinophilic respiratory inflammation and reactions to aspirin, each involving the marked overproduction of cysLTs. Here we demonstrate that the type 2 cysLT receptor (CysLT2R), which is not targeted by available drugs, is required in two different models to amplify eosinophilic airway inflammation via induced expression of IL-33 by lung epithelial cells. Endogenously generated cysLTs induced eosinophilia and expanded group 2 innate lymphoid cells (ILC2s) in aspirin-exacerbated respiratory disease-like Ptges-/- mice. These responses were mitigated by deletions of either Cysltr2 or leukotriene C4 synthase (Ltc4s). Administrations of either LTC4 (the parent cysLT) or the selective CysLT2R agonist N-methyl LTC4 to allergen sensitized wild-type mice markedly boosted ILC2 expansion and IL-5/IL-13 generation in a CysLT2R-dependent manner. Expansion of ILC2s and IL-5/IL-13 generation reflected CysLT2R-dependent production of IL-33 by alveolar type 2 cells, which engaged in a bilateral feed-forward loop with ILC2s. Deletion of Cysltr1 blunted LTC4-induced ILC2 expansion and eosinophilia but did not alter IL-33 induction. Pharmacological blockade of CysLT2R prior to inhalation challenge of Ptges-/- mice with aspirin blocked IL-33-dependent mast cell activation, mediator release, and changes in lung function. Thus, CysLT2R signaling, IL-33-dependent ILC2 expansion, and IL-33-driven mast cell activation are necessary for induction of type 2 immunopathology and aspirin sensitivity. CysLT2R-targeted drugs may interrupt these processes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aspirin / immunology*
  • Asthma, Aspirin-Induced / immunology
  • Asthma, Aspirin-Induced / pathology*
  • Cysteine / biosynthesis
  • Eosinophilia / immunology
  • Eosinophilia / pathology
  • Epithelial Cells / metabolism
  • Glutathione Transferase / genetics
  • Interleukin-13 / biosynthesis
  • Interleukin-33 / biosynthesis
  • Interleukin-33 / immunology*
  • Interleukin-5 / biosynthesis
  • Leukotriene E4 / biosynthesis
  • Leukotrienes / biosynthesis
  • Lung / pathology
  • Male
  • Mast Cells / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Prostaglandin-E Synthases / genetics
  • Receptors, Leukotriene / genetics
  • Receptors, Leukotriene / immunology*


  • Il33 protein, mouse
  • Interleukin-13
  • Interleukin-33
  • Interleukin-5
  • Leukotrienes
  • Receptors, Leukotriene
  • cysteinyl-leukotriene
  • Leukotriene E4
  • cysteinyl leukotriene receptor 2
  • Glutathione Transferase
  • leukotriene-C4 synthase
  • Prostaglandin-E Synthases
  • Ptges protein, mouse
  • Cysteine
  • Aspirin