12/15-Lipoxygenase Regulates IL-33-Induced Eosinophilic Airway Inflammation in Mice

Jun Miyata, Yoshiyuki Yokokura, Kazuyo Moro, Hiroyuki Arai, Koichi Fukunaga, Makoto Arita

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)


Dysregulated fatty acid metabolism is clinically associated with eosinophilic allergic diseases, including severe asthma and chronic rhinosinusitis. This study aimed to demonstrate the role of 12/15-lipoxygenase (12/15-LOX) in interleukin (IL)-33-induced eosinophilic airway inflammation; to this end, we used 12/15-LOX-deficient mice, which displayed augmented IL-33-induced lung inflammation, characterized by an increased number of infiltrated eosinophils and group 2 innate lymphoid cells (ILC2s) in the airway. Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based lipidomics revealed that the levels of a series of 12/15-LOX-derived metabolites were significantly decreased, and application of 14(S)-hydroxy docosahexaenoic acid (HDoHE), a major 12/15-LOX-derived product, suppressed IL-33-mediated eosinophilic inflammation in 12/15-LOX-deficient mice. Using bioactive lipid screening, we found that 14(S)-HDoHE and 10(S),17(S)-diHDoHE markedly attenuated ILC2 proliferation and cytokine production at micromolar concentration in vitro. In addition, maresin 1 (MaR1) and resolvin D1 (RvD1), 12/15-LOX-derived specialized proresolving mediators (SPMs), inhibited cytokine production of ILC2s at nanomolar concentration. These findings demonstrate the protective role of endogenous 12/15-LOX-derived lipid mediators in controlling ILC2-mediated eosinophilic airway inflammation and related diseases. Thus, 12/15-LOX-derived lipid mediators may represent a potential therapeutic strategy for ameliorating airway inflammation-associated conditions.

Original languageEnglish
Article number687192
JournalFrontiers in Immunology
Publication statusPublished - 2021 May 19


  • 12/15-lipoxygenase
  • 14(S)-HDoHE
  • IL-33
  • docosahexaenoic acid
  • group 2 innate lymphoid cell
  • lipidomics
  • maresin
  • specialized proresolving mediator

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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