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

doi:10.1016/j.jaci.2015.10.003

Journal of Allergy and Clinical Immunology

Volume 137, Issue 5, May 2016, Pages 1545-1556.e11

https://doi.org/10.1016/j.jaci.2015.10.003 Get rights and content

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.

Section snippets

Cell culture and treatments

Normal human bronchial epithelial (NHBE) cells were obtained from Lonza (Allendale, NJ) and cultured according to established protocols. Immortalized bronchial epithelial HBE1 cells were cultured, as previously described.²⁴ MTE cells were isolated from either wild-type (WT) C57BL/6 mice or Duox1^−/− mice²⁵ and cultured, as described previously.26, 27 Primary human nasal epithelial (HNE) cells were isolated from healthy volunteers and patients with allergic rhinitis and cultured, as recently

DUOX1 mediates airway epithelial secretion of IL-33 in response to allergen challenge

We evaluated epithelial cytokine production by NHBE cells in response to extracts of 2 important airborne allergens that have been associated with asthma: A alternata and Dermatophagoides pteronyssinus (HDM).31, 32 As expected,¹⁶ exposure of NHBE cells to extracts of A alternata induced rapid release of IL-33, reaching maximal levels after 2 hours, whereas secretion of other T_H2-inducing cytokines (IL-25 and TSLP), as well as the neutrophil chemokine IL-8/CXCL8, was more modest or delayed (Fig 1

Discussion

The IL-1 family member IL-33 has emerged as an important cytokine in innate type 2 immune responses to various allergens and helminths and is thought to play a major role in the pathophysiology of allergic diseases, such as asthma and rhinosinusitis.11, 42 However, the molecular mechanisms involved in cellular release of IL-33 have remained largely elusive and might involve regulated mechanisms rather than passive release caused by cell necrosis.16, 17 The present findings are highly

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: Supported by National Institutes of Health grants R01 HL085646 and ES021476 (to A.v.d.V.), R01 HL060014 (to Y.M.W.J.-H.), and IDeA-COBRE grant P30 GM103532.

: Disclosure of potential conflict of interest: Y. M. W. Janssen-Heininger has received research support from the National Institutes of Health (NIH; HL060014). A. E. Dixon is a board member for Roche, has received research support from Pfizer, and has received royalties from Springer and Henry Stewart Talks. M. Geiszt has received research support and travel support through a “Momentum” grant from the Hungarian Academy of Sciences. A. van der Vliet has received research support from the NIH/National Heart, Lung, and Blood Institute (NHLBI646) and has a patent related to the detection of S-nitrosylated proteins. The rest of the authors declare that they have no relevant conflicts of interest.

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Mechanisms of allergy and clinical immunologyAirway epithelial dual oxidase 1 mediates allergen-induced IL-33 secretion and activation of type 2 immune responses

Background

Objective

Methods

Results

Conclusion

Section snippets

Cell culture and treatments

DUOX1 mediates airway epithelial secretion of IL-33 in response to allergen challenge

Discussion

J Allergy Clin Immunol

J Allergy Clin Immunol

Curr Opin Immunol

Curr Opin Immunol

Blood

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J Allergy Clin Immunol

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J Allergy Clin Immunol

J Allergy Clin Immunol

Mucosal Immunol

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