Aspirin-Exacerbated Respiratory Disease Involves a Cysteinyl Leukotriene-Driven IL-33-Mediated Mast Cell Activation Pathway.

Abstract

Aspirin-exacerbated respiratory disease (AERD), a severe eosinophilic inflammatory disorder of the airways, involves overproduction of cysteinyl leukotrienes (cysLTs), activation of airway mast cells (MCs), and bronchoconstriction in response to nonselective cyclooxygenase inhibitors that deplete homeostatic PGE2. The mechanistic basis for MC activation in this disorder is unknown. We now demonstrate that patients with AERD have markedly increased epithelial expression of the alarmin-like cytokine IL-33 in nasal polyps, as compared with polyps from aspirin-tolerant control subjects. The murine model of AERD, generated by dust mite priming of mice lacking microsomal PGE2 synthase (ptges(-/-) mice), shows a similar upregulation of IL-33 protein in the airway epithelium, along with marked eosinophilic bronchovascular inflammation. Deletion of leukotriene C4 synthase, the terminal enzyme needed to generate cysLTs, eliminates the increased IL-33 content of the ptges(-/-) lungs and sharply reduces pulmonary eosinophilia and basal secretion of MC products. Challenges of dust mite-primed ptges(-/-) mice with lysine aspirin induce IL-33-dependent MC activation and bronchoconstriction. Thus, 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.

• Authors: Tao Liu, Yoshihide Kanaoka, Nora A Barrett, Chunli Feng, Denise Garofalo, Juying Lai, Kathleen Buchheit, Neil Bhattacharya, Tanya M Laidlaw, Howard R Katz, Joshua A Boyce
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 195 Issue 8 Pg. 3537-45 (Oct 15 2015) ISSN: 1550-6606 [Electronic] United States
• PMID: 26342029 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 by The American Association of Immunologists, Inc.

Chemical References

• IL33 protein, human
• Il33 protein, mouse
• Interleukin-33
• Leukotrienes
• Intramolecular Oxidoreductases
• PTGES protein, human
• Prostaglandin-E Synthases
• Ptges protein, mouse
• Dinoprostone

Topics

• Adolescent
• Adult
• Aged
• Animals
• Asthma, Aspirin-Induced (genetics, immunology, pathology)
• Dinoprostone (genetics, immunology)
• Female
• Humans
• Immunity, Innate
• Interleukin-33 (genetics, immunology)
• Intramolecular Oxidoreductases (genetics, immunology)
• Leukotrienes (genetics, immunology)
• Male
• Mast Cells (immunology, pathology)
• Mice
• Mice, Knockout
• Middle Aged
• Prostaglandin-E Synthases
• Pulmonary Eosinophilia (genetics, immunology, pathology)