Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
Department of Pulmonary Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
J Allergy Clin Immunol. 2014 Nov;134(5):1163-74.e16. doi: 10.1016/j.jaci.2014.04.035. Epub 2014 Jun 17.
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.
We sought to characterize MDSC accumulation and pathogenic functions in allergic airway inflammation mediated by COX-1 deficiency or aspirin treatment in mice.
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.
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 TH2 airway responses. The TH2-suppressive function of PMN-MDSCs was notably impaired by COX-1 deletion or inhibition, predominantly through downregulation of arginase-1. COX-1-derived prostaglandin E2 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 E2/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.
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.
髓系来源抑制细胞（MDSCs）最近被牵连到哮喘的发病机制中，但它们在阿司匹林不耐受性哮喘（AIA）患者中的调节仍不清楚。
我们试图描述 COX-1 缺乏或阿司匹林治疗在介导小鼠过敏气道炎症中 MDSC 聚集和致病功能。
通过卵清蛋白挑战诱导小鼠过敏气道炎症。通过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。
在过敏原挑战的小鼠中，募集到肺部的 CD11b(+)Gr1(high)Ly6G(+)Ly6C(int) MDSCs（多形核 MDSCs [PMN-MDSCs]）与气道炎症呈负相关。阿司匹林治疗和 COX-1 敲除（KO）小鼠在炎症肺和免疫器官中 PMN-MDSC 的积累明显减少，伴有 TH2 气道反应增加。PMN-MDSC 的 TH2 抑制功能主要通过下调精氨酸酶-1而明显受损。COX-1 衍生的前列腺素 E2 通过 E 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 小鼠中 PMN-MDSC 的精氨酸酶-1表达受损是通过前列腺素 E2/EP4/cAMP/蛋白激酶 A 途径的失调介导的。EP4 激动剂给药减轻了 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-MDSC 的免疫抑制功能显著降低。
在过敏原挑战的 COX-1 KO 小鼠和 AIA 患者中，PMN-MDSC 的免疫抑制活性降低，可能通过 EP4 介导的信号通路，表明激活 PMN-MDSC 可能是哮喘，特别是 AIA 的一种有前途的治疗策略。
