Oxidative stress serves as a key checkpoint for IL-33 release by airway epithelium

M. Uchida, E. L. Anderson, D. L. Squillace, N. Patil, P. J. Maniak, K. Iijima, H. Kita, S. M. O'Grady

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

Background: Interleukin (IL)-33 is implicated in the pathophysiology of asthma and allergic diseases. However, our knowledge is limited regarding how IL-33 release is controlled. The transcription factor nuclear factor-erythroid-2-related factor 2 (Nrf2) plays a key role in antioxidant response regulation. Objective: The goal of this project was to investigate the role of cellular oxidative stress in controlling IL-33 release in airway epithelium. Methods: Complementary approaches were used that included human bronchial epithelial cells and mouse models of airway type-2 immunity that were exposed to fungus Alternaria extract. The clinically available Nrf2 activator 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid methyl ester (CDDO-Me) was used to evaluate the role of Nrf2-induced antioxidant molecules. Results: Human bronchial epithelial cells produced reactive oxygen species (ROS) when they were exposed to Alternaria extract. ROS scavengers, such as glutathione (GSH) and N-acetyl cysteine, prevented extracellular secretion of ATP and increases in intracellular calcium concentrations that precede IL-33 release. Administration of CDDO-Me to mice enhanced expression of a number of antioxidant molecules in the lungs and elevated lung levels of endogenous GSH. Importantly, CDDO-Me treatment reduced allergen-induced ATP secretion and IL-33 release by airway epithelial cells in vitro and protected mice from IL-33 release and asthma-like pathological changes in the lungs. Conclusions: The balance between oxidative stress and antioxidant responses plays a key role in controlling IL-33 release in airway epithelium. The therapeutic potential of Nrf2 activators needs to be considered for asthma and allergic airway diseases.

Original languageEnglish (US)
Pages (from-to)1521-1531
Number of pages11
JournalAllergy: European Journal of Allergy and Clinical Immunology
Volume72
Issue number10
DOIs
StatePublished - Oct 2017

Bibliographical note

Funding Information:
MU is a recipient of 2012 Banyu Life Science Foundation International Fellowship. We thank Dr. Andrew N. McKenzie for providing the Il1rl1?/? mice and LuRaye S. Eischens for secretarial help. This work was supported by grants from the National Institutes of Health (R01 AI71106, R01 HL117823, AI128729) and the Mayo Foundation.

Keywords

  • IL-33
  • airway epithelial cells
  • asthma
  • lung
  • nuclear factor-erythroid-2-related factor 2
  • reactive oxygen species

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