Aspirin Exacerbated Respiratory Disease Involves a Cysteinyl Leukotriene-Driven IL-33-Mediated Mast Cell Activation Pathway
Sunday, March 6, 2016: 4:45 PM
Concourse Foyer (Convention Center)
Tao Liu, PhD, Yoshihide Kanaoka, MD PhD, Nora A. Barrett, MD FAAAAI, Chunli Feng, MD, Denise Garofalo, Juying Lai, Kathleen M. Buchheit, MD, Neil Bhattacharyya, MD, Tanya M. Laidlaw, MD, Howard Katz, PhD, Joshua A. Boyce, MD FAAAAI
Rationale: Aspirin exacerbated respiratory disease (AERD) involves overproduction of cysteinyl-leukotrienes (cysLTs), activation of airway mast cells (MCs), and bronchoconstriction in response to nonselective-cyclooxygenase inhibitors. The mechanistic basis for MC activation in this disorder is unknown, but can be inhibited by inhibition of cysLT synthesis, suggesting MC activation in AERD occurs by an idiosyncratic, cysLTs-dependent mechanism. IL-33, a cytokine released by structural cells, can activate MCs. Previously we have demonstrated that ptges-/- mice show increased bronchoconstriction in response to inhaled lysine-aspirin (Lys-ASA). We hypothesized that AERD involves a cysLTs-driven IL-33-mediated mast cell activation pathway.

Methods: Nasal polyps were collected from AERD patients and aspirin tolerant (AT) controls for IL-33 analysis. ptges-/- and ltc4s-/- mice were primed with dust-mite-extract, and then challenged with aerosol Lys-ASA or exogenous cysLTs to record airway resistance (RL). Lung MC activation and eicosanoids production were measured by ELISA. IL-33 level was measured by ELISA and Western-Blot.

Results: AERD patients show increased IL-33 expression in nasal polyps, as compared to controls. The murine model of AERD (ptges-/- mice), shows upregulated IL-33 protein level in the airway epithelium, along with marked eosinophilic bronchovascular inflammation. Deletion of LTC4-synthase attenuated the increased IL-33 content of the ptges-/- lungs and reduced pulmonary eosinophilia and basal secretion of MC products. Challenges of dust mite-primed ptges-/- mice with Lys-ASA induce IL-33-dependent MC activation and bronchoconstriction that were reproduced with LTE4 challenges.

Conclusions: IL-33 is a component of a cysLT-driven innate type-2 immune response that drives pathogenic MC activation and contributes substantially to AERD pathogenesis.