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

Frontiers in Immunology

Makoto Arita¹  Jun Miyata²  Koichi Fukunaga⁴  Hiroyuki Arai⁵  Yoshiyuki Yokokura⁵  Kazuyo Moro⁷ 

[1]Cellular and Molecular Epigenetics Laboratory, Graduate School of Medical Life Science, Yokohama City University, Yokohama, Japan

[2]Division of Infectious Diseases and Respiratory Medicine, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan

[3]Division of Physiological Chemistry and Metabolism, Keio University Faculty of Pharmacy, Tokyo, Japan

[4]Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan

[5]Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan

[6]Laboratory for Innate Immune Systems, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan

[7]Laboratory for Innate Immune Systems, Immunology Frontier Research Center, Osaka University, Osaka, Japan

[8]Laboratory for Innate Immune Systems, RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Japan

[9]Laboratory of Metabolomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

关键词: 12/15-lipoxygenase;    IL-33;    docosahexaenoic acid;    14(S)-HDoHE;    group 2 innate lymphoid cell;    lipidomics;   

DOI  :  10.3389/fimmu.2021.687192

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown