Prostaglandin D2 metabolites activate asthmatic patient-derived type 2 innate lymphoid cells and eosinophils via the DP2 receptor

BackgroundProstaglandin D2(PGD2) signaling via prostaglandin D2receptor 2 (DP2) contributes to atopic and non-atopic asthma. Inhibiting DP2has shown therapeutic benefit in certain subsets of asthma patients, improving eosinophilic airway inflammation. PGD2metabolites prolong the inflammatory response in asthmatic patients via DP2signaling. The role of PGD2metabolites on eosinophil and ILC2 activity is not fully understood.MethodsEosinophils and ILC2s were isolated from peripheral blood of atopic asthmatic patients. Eosinophil shape change, ILC2 migration and IL-5/IL-13 cytokine secretion were measured after stimulation with seven PGD2metabolites in presence or absence of the selective DP2antagonist fevipiprant.ResultsSelected metabolites induced eosinophil shape change with similar nanomolar potencies except for 9α,11β-PGF2. Maximal values in forward scatter of eosinophils were comparable between metabolites. ILC2s migrated dose-dependently in the presence of selected metabolites except for 9α,11β-PGF2with EC50values ranging from 17.4 to 91.7 nM. Compared to PGD2, the absolute cell migration was enhanced in the presence of Δ12-PGD2, 15-deoxy-Δ12,14-PGD2, PGJ2, Δ12-PGJ2and 15-deoxy-Δ12,14-PGJ2. ILC2 cytokine production was dose dependent as well but with an average sixfold reduced potency compared to cell migration (IL-5 range 108.1 to 526.9 nM, IL-13 range: 125.2 to 788.3 nM). Compared to PGD2, the absolute cytokine secretion was reduced in the presence of most metabolites. Fevipiprant dose-dependently inhibited eosinophil shape change, ILC2 migration and ILC2 cytokine secretion with (sub)-nanomolar potencies.ConclusionProstaglandin D2metabolites initiate ILC2 migration and IL-5 and IL-13 cytokine secretion in a DP2dependent manner. Our data indicate that metabolites may be important for in vivo eosinophil activation and ILC2 migration and to a lesser extent for ILC2 cytokine secretion.