Airway epithelial dual oxidase 1 mediates allergen-induced IL-33 secretion and activation of type 2 immune responses

J Allergy Clin Immunol. 2016 May;137(5):1545-1556.e11. doi: 10.1016/j.jaci.2015.10.003. Epub 2015 Nov 17.


Background: The IL-1 family member IL-33 plays a critical role in type 2 innate immune responses to allergens and is an important mediator of allergic asthma. The mechanisms by which allergens provoke epithelial IL-33 secretion are still poorly understood.

Objective: Based on previous findings indicating involvement of the NADPH oxidase dual oxidase 1 (DUOX1) in epithelial wound responses, we explored the potential involvement of DUOX1 in allergen-induced IL-33 secretion and potential alterations in airways of asthmatic patients.

Methods: Cultured human or murine airway epithelial cells or mice were subjected to acute challenge with Alternaria alternata or house dust mite, and secretion of IL-33 and activation of subsequent type 2 responses were determined. The role of DUOX1 was explored by using small interfering RNA approaches and DUOX1-deficient mice. Cultured nasal epithelial cells from healthy subjects or asthmatic patients were evaluated for DUOX1 expression and allergen-induced responses.

Results: In vitro or in vivo allergen challenge resulted in rapid airway epithelial IL-33 secretion, which depended critically on DUOX1-mediated activation of epithelial epidermal growth factor receptor and the protease calpain-2 through a redox-dependent mechanism involving cysteine oxidation within epidermal growth factor receptor and the tyrosine kinase Src. Primary nasal epithelial cells from patients with allergic asthma were found to express increased DUOX1 and IL-33 levels and demonstrated enhanced IL-33 secretion in response to allergen challenge compared with values seen in nasal epithelial cells from nonasthmatic subjects.

Conclusion: Our findings implicate epithelial DUOX1 as a pivotal mediator of IL-33-dependent activation of innate airway type 2 immune responses to common airborne allergens and indicate that enhanced DUOX1 expression and IL-33 secretion might present important contributing features of allergic asthma.

Keywords: Asthma; H(2)O(2); IL-13; Src; epidermal growth factor receptor; redox signaling.

MeSH terms

  • Allergens / immunology*
  • Alternaria / immunology
  • Animals
  • Bronchoalveolar Lavage Fluid
  • Cell Line
  • Cells, Cultured
  • Dual Oxidases
  • Epithelial Cells / immunology
  • ErbB Receptors / immunology
  • Humans
  • Interleukin-33 / immunology*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NADPH Oxidases / genetics
  • NADPH Oxidases / immunology*
  • Pyroglyphidae / immunology
  • RNA, Small Interfering / genetics
  • Rhinitis, Allergic / immunology*


  • Allergens
  • IL33 protein, human
  • Il33 protein, mouse
  • Interleukin-33
  • RNA, Small Interfering
  • Dual Oxidases
  • NADPH Oxidases
  • DUOX1 protein, human
  • Duox1 protein, mouse
  • ErbB Receptors