Fraunhofer Institute of Toxicology and Experimental Medicine, Hannover, Germany.
German Center for Lung Research (DZL-BREATH), Hannover, Germany.
PLoS One. 2024 Jul 25;19(7):e0307750. doi: 10.1371/journal.pone.0307750. eCollection 2024.
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. Blockade of DP2 has shown therapeutic benefit in subsets of asthma patients. Cellular mechanisms of ILC2 activity in response to PGD2 and its metabolites are still unclear. We hypothesized that ILC2 respond non-uniformly to PGD2 metabolites. ILC2s were isolated from peripheral blood of patients with atopic asthma. ILC2s were stimulated with PGD2 and four PGD2 metabolites (Δ12-PGJ2, Δ12-PGD2, 15-deoxyΔ12,14-PGD2, 9α,11β-PGF2) with or without the selective DP2 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 PGD2 (14 DEGs), Δ12-PGD2 (27 DEGs), 15-deoxyΔ12,14-PGD2 (56 DEGs) and Δ12-PGJ2 (136 DEGs), but not with 9α,11β-PGF2. Common upregulated DEGs were i.e. ARG2, SLC43A2, LAYN, IGFLR1, or EPHX2. Inhibition of DP2 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 PGD2 metabolite-induced immune responses in ILC2s as well as the anti-inflammatory effects of DP2 inhibition via fevipiprant. Furthermore, PGD2 and metabolites showed distinct profiles in ILC2 activation. Overall, these results expand our understanding of DP2 initiated ILC2 activity.
前列腺素 D2（PGD2）的产生增加与哮喘和过敏的发展和进展有关。PGD2 迅速降解为其代谢物，这些代谢物以 PGD2 受体 2（DP2）依赖性方式启动 2 型先天淋巴样细胞（ILC2）迁移和 IL-5/IL-13 细胞因子分泌。DP2 的阻断在哮喘患者亚组中显示出治疗益处。PGD2 及其代谢物诱导 ILC2 活性的细胞机制仍不清楚。我们假设 ILC2 对 PGD2 代谢物的反应不一致。从特应性哮喘患者的外周血中分离出 ILC2。用 PGD2 和四种 PGD2 代谢物（Δ12-PGJ2、Δ12-PGD2、15-脱氧Δ12,14-PGD2、9α,11β-PGF2）刺激 ILC2，或不使用选择性 DP2 拮抗剂 fevipiprant。通过 DeSeq2 对总 RNA 进行测序，并鉴定差异表达基因（DEG）。差异基因表达分析显示，PGD2（14 个 DEG）、Δ12-PGD2（27 个 DEG）、15-脱氧Δ12,14-PGD2（56 个 DEG）和 Δ12-PGJ2（136 个 DEG）刺激的 ILC2 中促炎 DEG 上调，但 9α,11β-PGF2 则不然。常见的上调 DEG 为 ARG2、SLC43A2、LAYN、IGFLR1 或 EPHX2。通过 fevipiprant 抑制 DP2 主要导致促炎基因如 DUSP4、SPRED2、DUSP6、ETV1、ASB2、CD38、ADGRG1、DDIT4、TRPM2 或 CD69 的下调。DEG 与迁移和各种免疫反应相关途径有关，如“趋化因子（C-C 基序）配体 4 产生”、“细胞迁移”、“白细胞介素-13 产生”、“通过 JAK-STAT 调节受体信号转导途径”或“淋巴细胞凋亡过程”，这强调了 PGD2 代谢物诱导的 ILC2 免疫反应中 DP2 诱导的促炎作用，以及通过 fevipiprant 抑制 DP2 的抗炎作用。此外，PGD2 和代谢物在 ILC2 激活中表现出不同的特征。总的来说，这些结果扩展了我们对 DP2 启动的 ILC2 活性的理解。
