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,以PGD2受体2(DP2)依赖性方式启动2型先天淋巴细胞(ILC2)迁移和IL-5/IL-13细胞因子分泌。阻断DP2已在哮喘患者的亚组中显示出治疗益处。ILC2活性响应PGD2及其代谢产物的细胞机制尚不清楚。我们假设ILC2对PGD2代谢物的反应不均匀。从特应性哮喘患者外周血中分离ILC2s。用PGD2和四种PGD2代谢物刺激ILC2s(Δ12-PGJ2,Δ12-PGD2,15-脱氧Δ12,14-PGD2,9α,11β-PGF2)有或没有选择性DP2拮抗剂feviprant。对总RNA进行测序,并通过DeSeq2鉴定了差异表达基因(DEG)。差异基因表达分析显示,用PGD2(14DEGs)刺激的ILC2s中促炎DEGs的上调,Δ12-PGD2(27度),15-脱氧Δ12,14-PGD2(56DEG)和Δ12-PGJ2(136DEG),但不是9α,11β-PGF2。常见的上调DEG为ARG2、SLC43A2、LAYN、IGFLR1或EPHX2。通过feviprant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。DEGs与迁移和各种免疫反应相关途径有关,例如“趋化因子(C-C基序)配体4的产生”,\"细胞迁移\",“白细胞介素13生产”,“通过JAK-STAT调节受体信号通路”,或“淋巴细胞凋亡过程”,强调PGD2代谢物在ILC2s中诱导的免疫反应的促炎作用以及通过feviprant抑制DP2的抗炎作用。此外,PGD2和代谢物在ILC2活化中显示不同的谱。总的来说,这些结果扩展了我们对DP2引发的ILC2活性的理解。
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.