Myeloid-derived suppressor cell function is diminished in aspirin-triggered allergic airway hyperresponsiveness in mice
Myeloid-derived suppressor cell function is diminished in aspirin-triggered allergic airway hyperresponsiveness in mice
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在阿司匹林引发的小鼠过敏性气道高反应性中，骨髓源性抑制细胞功能减弱。
DOI：
10.1016/j.jaci.2014.04.035
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发表时间：
2014-11-01
影响因子：
14.2
通讯作者：
Yu, Ying
中科院分区：
文献类型：
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作者：
Shi, Maohua;Shi, Guochao;Yu, Ying
背景：骨髓源性抑制细胞（MDSC）最近被认为与哮喘的发病机制有关，但其在阿司匹林不耐受哮喘（AIA）患者中的调节仍不清楚。目的：我们试图表征 COX-1 缺乏或阿司匹林治疗介导的小鼠过敏性气道炎症中 MDSC 的积累和致病功能。 通过卵清蛋白激发在小鼠中诱导。使用流式细胞术和药理学/基因操作方法分析小鼠中 MDSC 的分布和功能。结果：CD11b(+)Gr1(high)Ly6G(+)Ly6C(int) MDSC（多形核 MDSC [PMN-MDSC]）招募到肺部与过敏原挑战的气道炎症呈负相关 老鼠。阿司匹林治疗和 COX-1 敲除 (KO) 小鼠在发炎的肺部和免疫器官中的 PMN-MDSC 积累显着降低，同时 T(H)2 气道反应增加。 COX-1 缺失或抑制显着损害 PMN-MDSC 的 T(H)2 抑制功能，主要是通过精氨酸酶 1 的下调。 COX-1 衍生的前列腺素 E-2 通过 E 类前列腺素 2 和 4 受体（EP2 和 EP4）促进骨髓中 PMN-MDSC 的生成，而 COX-1 KO 小鼠 PMN-MDSC 中精氨酸酶 1 表达受损是由前列腺素 E-2/EP4/环 AMP/蛋白激酶 A 通路失调介导的。 EP4 激动剂给药可减轻 COX-1 KO 小鼠过敏引起的气道高反应性。此外，与阿司匹林耐受性哮喘患者相比，AIA患者的PMN-MDSCs的免疫抑制功能显着下降。结论：在过敏原攻击的COX-1 KO小鼠和AIA患者中，PMN-MDSCs的免疫抑制活性均减弱，可能是通过EP4介导的信号通路，表明PMN-MDSCs的激活可能 是一种有前途的哮喘治疗策略，特别是 AIA。
Background: Myeloid-derived suppressor cells (MDSCs) have recently been implicated in the pathogenesis of asthma, but their regulation in patients with aspirin-intolerant asthma (AIA) remains unclear.Objective: We sought to characterize MDSC accumulation and pathogenic functions in allergic airway inflammation mediated by COX-1 deficiency or aspirin treatment in mice.Methods: Allergic airway inflammation was induced in mice by means of ovalbumin challenge. The distribution and function of MDSCs in mice were analyzed by using flow cytometry and pharmacologic/gene manipulation approaches.Results: CD11b(+)Gr1(high)Ly6G(+)Ly6C(int) MDSCs (polymorphonuclear MDSCs [PMN-MDSCs]) recruited to the lungs are negatively correlated with airway inflammation in allergen-challenged mice. Aspirin-treated and COX-1 knockout (KO) mice showed significantly lower accumulation of PMN-MDSCs in the inflamed lung and immune organs accompanied by increased T(H)2 airway responses. The T(H)2-suppressive function of PMN-MDSCs was notably impaired by COX-1 deletion or inhibition, predominantly through downregulation of arginase-1. COX-1-derived prostaglandin E-2 promoted PMN-MDSC generation in bone marrow through E prostanoid 2 and 4 receptors (EP2 and EP4), whereas the impaired arginase-1 expression in PMN-MDSCs in COX-1 KO mice was mediated by dysregulation of the prostaglandin E-2/EP4/cyclic AMP/protein kinase A pathway. EP4 agonist administration alleviated allergy-induced airway hyperresponsiveness in COX-1 KO mice. Moreover, the immunosuppressive function of PMN-MDSCs from patients with AIA was dramatically decreased compared with that from patients with aspirin-tolerant asthma.Conclusion: The immunosuppressive activity of PMN-MDSCs was diminished in both allergen-challenged COX-1 KO mice and patients with AIA, probably through an EP4-mediated signaling pathway, indicating that activation of PMN-MDSCs might be a promising therapeutic strategy for asthma, particularly AIA.