Prostaglandin D.sub.2 receptor 2 downstream signaling and modulation of type 2 innate lymphoid cells from patients with asthma

• Published in: PloS one 2024-07, Vol.19 (7), p.e0307750
• Main Authors: Gress, Christina, Fuchs, Maximilian, Carstensen-Aurèche, Saskia, Müller, Meike, Hohlfeld, Jens M
• Format: Article
• Language: English
• Subjects: Asthma; Gene expression; Genes; Health aspects; Interleukins; Lymphocytes; Metabolites; Prostaglandins; RNA
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0307750

Increased production of Prostaglandin D.sub.2 (PGD.sub.2) is linked to development and progression of asthma and allergy. PGD.sub.2 is rapidly degraded to its metabolites, which initiate type 2 innate lymphoid cells (ILC2) migration and IL-5/IL-13 cytokine secretion in a PGD.sub.2 receptor 2 (DP.sub.2 )-dependent manner. Blockade of DP.sub.2 has shown therapeutic benefit in subsets of asthma patients. Cellular mechanisms of ILC2 activity in response to PGD.sub.2 and its metabolites are still unclear. We hypothesized that ILC2 respond non-uniformly to PGD.sub.2 metabolites. ILC2s were isolated from peripheral blood of patients with atopic asthma. ILC2s were stimulated with PGD.sub.2 and four PGD.sub.2 metabolites ([DELTA].sup.12 -PGJ.sub.2, [DELTA].sup.12 -PGD.sub.2, 15-deoxy[DELTA].sup.12,14 -PGD.sub.2, 9[alpha],11[beta]-PGF.sub.2) with or without the selective DP.sub.2 antagonist fevipiprant. Total RNA was sequenced, and differentially expressed genes (DEG) were identified by DeSeq2. Differential gene expression analysis revealed an upregulation of pro-inflammatory DEGs in ILC2s stimulated with PGD.sub.2 (14 DEGs), [DELTA].sup.12 -PGD.sub.2 (27 DEGs), 15-deoxy[DELTA].sup.12,14 -PGD.sub.2 (56 DEGs) and [DELTA].sup.12 -PGJ.sub.2 (136 DEGs), but not with 9[alpha],11[beta]-PGF.sub.2 . Common upregulated DEGs were i.e. ARG2, SLC43A2, LAYN, IGFLR1, or EPHX2. Inhibition of DP.sub.2 via fevipiprant mainly resulted in downregulation of pro-inflammatory genes such as DUSP4, SPRED2, DUSP6, ETV1, ASB2, CD38, ADGRG1, DDIT4, TRPM2, or CD69. DEGs were related to migration and various immune response-relevant pathways such as "chemokine (C-C motif) ligand 4 production", "cell migration", "interleukin-13 production", "regulation of receptor signaling pathway via JAK-STAT", or "lymphocyte apoptotic process", underlining the pro-inflammatory effects of PGD.sub.2 metabolite-induced immune responses in ILC2s as well as the anti-inflammatory effects of DP.sub.2 inhibition via fevipiprant. Furthermore, PGD.sub.2 and metabolites showed distinct profiles in ILC2 activation. Overall, these results expand our understanding of DP.sub.2 initiated ILC2 activity.