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

Background Prostaglandin D 2 (PGD 2 ) signaling via prostaglandin D 2 receptor 2 (DP 2 ) contributes to atopic and non-atopic asthma. Inhibiting DP 2 has shown therapeutic benefit in certain subsets of asthma patients, improving eosinophilic airway inflammation. PGD 2 metabolites prolong the inflammatory response in asthmatic patients via DP 2 signaling. The role of PGD 2 metabolites on eosinophil and ILC2 activity is not fully understood. Methods Eosinophils 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 PGD 2 metabolites in presence or absence of the selective DP 2 antagonist fevipiprant. Results Selected metabolites induced eosinophil shape change with similar nanomolar potencies except for 9α,11β-PGF 2 . 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-PGF 2 with EC 50 values ranging from 17.4 to 91.7 nM. Compared to PGD 2 , the absolute cell migration was enhanced in the presence of Δ 12 -PGD 2 , 15-deoxy-Δ 12,14 -PGD 2 , PGJ 2 , Δ 12 -PGJ 2 and 15-deoxy-Δ 12,14 -PGJ 2 . 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 PGD 2 , 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. Conclusion Prostaglandin D 2 metabolites initiate ILC2 migration and IL-5 and IL-13 cytokine secretion in a DP 2 dependent 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.