17,18-epoxyeicosatetraenoic acid and its metabolite attenuate IL-33-induced airway inflammation involving group 2 innate lymphoid cells

Group 2 innate lymphoid cells (ILC2s) play critical roles in type 2 airway inflammation. 17,18-epoxyeicosatetraenoic acid (17,18-EpETE), an eicosapentaenoic acid metabolite, is generated from dietary omega-3 fatty acids, and may have anti-inflammatory activities. We evaluated the effect of 17,18-EpETE and its metabolite, 17,18-dihydroxy-eicosa-5,8,11,14-tetraenoic acid (17,18-diHETE), on IL-33-induced airway inflammation involving ILC2s. We evaluated the in vitro effects of 17,18-EpETE and 17,18-diHETE on the IL-33-induced production of IL-5 and IL-13 by human ILC2s (isolated from peripheral blood) using ELISA. Expression of the corresponding fatty acid receptors and the GATA-3 transcription factor were examined using flow cytometry and quantitative RT-PCR. Additionally, we examined the in vivo effects of 17,18-EpETE or 17,18-diHETE in a mouse model of type 2 airway inflammation induced by intranasal (i.n.) instillation of IL-33. 17,18-EpETE or 17,18-diHETE inhibited IL-33-induced production of IL-5 and IL-13, and IL-33-induced expression of GATA-3 in human ILC2s. GW1100, an antagonist of G protein-coupled receptor (GPR) 40, or GW9662, an antagonist of peroxisome proliferator-activated receptor γ (PPARγ), counteracted the inhibitory effects of 17,18-EpETE or 17,18-diHETE on the IL-33-induced production of IL-5 and IL-13 by ILC2s. I.n. administration of 17,18-EpETE or 17,18-diHETE attenuated IL-33-induced eosinophil infiltration and mucus production in mouse nasal mucosa, and production of IL-5 and IL-13 in lung tissue and bronchoalveolar lavage fluid. The present study demonstrated the anti-inflammatory effects of 17,18-EpETE and 17,18-diHETE on IL-33-induced airway inflammation involving ILC2s. I.n. administration of 17,18-EpETE may be a new therapeutic approach for the treatment of intractable type 2 airway inflammation.