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Saskia Carstensen, Christina Gress, Veit J Erpenbeck, Shamsah D Kazani, Jens M Hohlfeld, David A Sandham, Meike Müller
Department of Biomarker Analysis and Development, Clinical Airway Research, Fraunhofer Institute of Toxicology and Experimental Medicine, Hannover, Germany.
Novartis Pharma AG, Basel, Switzerland.
Respir Res. 2021 Oct 7;22(1):262. doi: 10.1186/s12931-021-01852-3.
Prostaglandin D (PGD) signaling via prostaglandin D receptor 2 (DP) contributes to atopic and non-atopic asthma. Inhibiting DP has shown therapeutic benefit in certain subsets of asthma patients, improving eosinophilic airway inflammation. PGD metabolites prolong the inflammatory response in asthmatic patients via DP signaling. The role of PGD metabolites on eosinophil and ILC2 activity is not fully understood.
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 metabolites in presence or absence of the selective DP antagonist fevipiprant.
Selected metabolites induced eosinophil shape change with similar nanomolar potencies except for 9α,11β-PGF. 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 with EC values ranging from 17.4 to 91.7 nM. Compared to PGD, the absolute cell migration was enhanced in the presence of Δ-PGD, 15-deoxy-Δ-PGD, PGJ, Δ-PGJ and 15-deoxy-Δ-PGJ. 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, 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.
Prostaglandin D metabolites initiate ILC2 migration and IL-5 and IL-13 cytokine secretion in a DP 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.
前列腺素 D（PGD）通过前列腺素 D 受体 2（DP）信号传导有助于特应性和非特应性哮喘。抑制 DP 在某些哮喘患者亚群中显示出治疗益处，可改善嗜酸性气道炎症。PGD 代谢物通过 DP 信号传导延长哮喘患者的炎症反应。PGD 代谢物对嗜酸性粒细胞和 ILC2 活性的作用尚未完全阐明。
从特应性哮喘患者的外周血中分离出嗜酸性粒细胞和 ILC2。在存在或不存在选择性 DP 拮抗剂 fevipiprant 的情况下，用七种 PGD 代谢物刺激后，测量嗜酸性粒细胞形态变化、ILC2 迁移和 IL-5/IL-13 细胞因子分泌。
所选代谢物诱导嗜酸性粒细胞形态变化的纳米摩尔效力相似，除 9α,11β-PGF 外。代谢物之间的前向散射最大值相似。除 9α,11β-PGF 外，所选代谢物呈剂量依赖性地诱导 ILC2 迁移，EC 值范围为 17.4 至 91.7 nM。与 PGD 相比，在 Δ-PGD、15-脱氧-Δ-PGD、PGJ、Δ-PGJ 和 15-脱氧-Δ-PGJ 存在下，绝对细胞迁移增强。ILC2 细胞因子产生也呈剂量依赖性，但与细胞迁移相比效力平均降低六倍（IL-5 范围 108.1 至 526.9 nM，IL-13 范围：125.2 至 788.3 nM）。与 PGD 相比，在大多数代谢物存在下，绝对细胞因子分泌减少。Fevipiprant 呈剂量依赖性抑制嗜酸性粒细胞形态变化、ILC2 迁移和 ILC2 细胞因子分泌，效力为（亚）纳摩尔。
前列腺素 D 代谢物以 DP 依赖性方式引发 ILC2 迁移和 IL-5 和 IL-13 细胞因子分泌。我们的数据表明，代谢物可能对体内嗜酸性粒细胞激活和 ILC2 迁移很重要，对 ILC2 细胞因子分泌的作用较小。
