Abstract
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.
Highlights
Asthma is a common disease affecting more than 300 million people worldwide, and the number of patients with asthma is rapidly increasing [1, 2]
Dysregulated metabolism of polyunsaturated fatty acids [arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA)] is observed in allergic diseases, including severe asthma and its related diseases, such as aspirinexacerbated respiratory disease and eosinophilic chronic rhinosinusitis [3, 4]. This abnormality is partly characterized by impaired synthesis of specialized proresolving mediators (SPMs; lipoxins (LXs; LXA4 and LXB4), protectins (PD1 and protectin DX (PDX)), resolvin D series (RvDs; resolvin D1 (RvD1)-6), and maresins (MaRs; maresin 1 (MaR1)-2), which promote the resolution of inflammation
We demonstrated that 12/15-LOX, a key enzyme for the biosynthesis of specialized pro-resolving lipid mediators (SPMs), conferred a protective effect on innate pulmonary eosinophilic inflammation in vivo
Summary
Asthma is a common disease affecting more than 300 million people worldwide, and the number of patients with asthma is rapidly increasing [1, 2]. Dysregulated metabolism of polyunsaturated fatty acids [arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA)] is observed in allergic diseases, including severe asthma and its related diseases, such as aspirinexacerbated respiratory disease and eosinophilic chronic rhinosinusitis [3, 4]. This abnormality is partly characterized by impaired synthesis of specialized proresolving mediators (SPMs; lipoxins (LXs; LXA4 and LXB4), protectins (PD1 and PDX), resolvin D series (RvDs; RvD1-6), and maresins (MaRs; MaR1-2), which promote the resolution of inflammation. These findings suggest the regulatory roles of 15-LOX and 12/15-LOX in eosinophilic inflammation in the lungs, the causal relationships between these enzymes and severe allergic diseases remain unclear
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