Background Increased production of Prostaglandin D2 (PGD2) is linked to development and progression of asthma and allergy. PGD2 is rapidly degraded to its metabolites, which initiate type 2 innate lymphoid cells (ILC2) migration and IL-5/IL-13 cytokine secretion in a PGD2 receptor 2 (DP2)-dependent manner. Inhibition of DP2 has shown therapeutic benefit in subsets of asthma patients. Cellular mechanisms of ILC2 activity in response to PGD2 metabolites are still unclear.
Methods ILC2s were isolated from peripheral blood of four patients with atopic asthma. ILC2s were stimulated with PGD2 and four PGD2 metabolites (?12PGJ2, ?12PGD2, 15-deoxy?12,14PGD2, 9?,11?PGF2) with or without the selective DP2 antagonist fevipiprant. Total RNA was sequenced, and differential expressed genes (DEG) were identified by DeSeq2.
Results Dynein axonemal heavy chain 1 (DNAH1) expression was significantly decreased in activated ILC2, while Layilin (LAYN) significantly increased mainly in response to ?12PGJ2. DP2 inhibition via fevipiprant resulted in six DEG (e.g. ?DDIT4, ?LAYN). Hypothesis-driven data analysis revealed elevation of ?2-integrin (CD18) and hematopoietic PGD synthase (HPGDS; exept for 9?,11?PGF2) in stimulated ILC2, which normalized post DP2 inhibition with fevipiprant.
Conclusions DNAH1 is involved in recurrent respiratory infections progressing to permanent lung damage, but its role for ILC2 regulation remains unclear. Increased CD18 and LAYN, both relevant for cell adhesion, may enhance ILC2 migration response. Elevated HPGDS would catalyze further PGD2 synthesis and thus increase inflammation. Our results further our understanding of DP2 initiated ILC2 activity.