痰microRNA筛选显示前列腺素EP3受体可作为变应原特异性免疫治疗的选择靶点
2021/10/20
摘要
背景：一些microRNA(miRs)已被描述为液体活检和过敏性哮喘的潜在生物标志物，但对miRs在气道表达的治疗作用仍不清楚。
方法：在本研究中，我们在草花粉过敏患者的痰液中研究了miR-相关的表观遗传机制，这些患者接受了或未接受了过敏原特异性免疫治疗(AIT)。使用 miR微阵列和相同样本的全转录组微阵列分析对健康对照(HC)、AIT 治疗和未治疗的草花粉过敏性鼻炎患者(AA)和无哮喘(AR) 的诱导痰样本进行分析。miR靶点在电脑中模拟中被预测，并用于识别逆调控。采用ELISA法检测局部PGE(2)水平。
结果：与HC患者相比，AA患者痰液中有259个miRs上调，只有1个miRs下调。在AIT治疗患者的诱导痰中观察到相反的图像:在哮喘患者AIT治疗后，21个miRs下调，只有4个miRs上调。在这4个miRs中，miR-3935最为突出，因为其预测的靶蛋白PTGER3(前列腺素EP3受体)在治疗AA患者中比未治疗AA患者下调。其配体PGE(2)在过敏性患者，尤其是哮喘患者的痰上清中水平升高，在AIT后下调。最后，局部PGE(2)水平与ILC2频率、痰中IL-13分泌水平、炎症细胞负荷、痰中嗜酸性粒细胞和症状负担相关。
结论：在研究过敏患者的痰液miR表达模式时，我们发现miR-3935与其预测的靶基因前列腺素E-3受体之间存在关联，该基因可能通过抑制PGE(2)-PTGER3轴介导AIT效应。
Sputum microRNA-screening reveals Prostaglandin EP3 receptor as selective target in allergen-specific immunotherapy
Jakwerth CA, Chaker AM, Guerth F, et al.
Abstract
BACKGROUND: Several microRNAs (miRs) have been described as potential biomarkers in liquid biopsies and in the context of allergic asthma, while therapeutic effects on the airway expression of miRs remain elusive.
METHODS:In this study, we investigated epigenetic miR-associated mechanisms in the sputum of grass pollen-allergic patients with and without allergen-specific immunotherapy (AIT). Induced sputum samples of healthy controls (HC), AIT-treated and untreated grass pollen-allergic rhinitis patients with (AA) and without asthma (AR) were profiled using miR microarray and whole-transcriptome microarray analysis of the same samples. miR targets were predicted in silico and used to identify inverse regulation. Local PGE (2) levels were measured using ELISA.
RESULTS:Two hundred and fifty-nine miRs were upregulated in the sputum of AA patients compared with HC, while only one was downregulated. The inverse picture was observed in induced sputum of AIT-treated patients: while 21 miRs were downregulated, only 4 miRs were upregulated in asthmatics upon AIT. Of these 4 miRs, miR-3935 stood out, as its predicted target PTGER3, the prostaglandin EP3 receptor, was downregulated in treated AA patients compared with untreated. The levels of its ligand PGE(2) in the sputum supernatants of these samples were increased in allergic patients, especially asthmatics, and downregulated after AIT. Finally, local PGE(2) levels correlated with ILC2 frequencies, secreted sputum IL-13 levels, inflammatory cell load, sputum eosinophils and symptom burden.
CONCLUSIONS: While profiling the sputum of allergic patients for novel miR expression patterns, we uncovered an association between miR-3935 and its predicted target gene, the prostaglandin E-3 receptor, which might mediate AIT effects through suppression of the PGE(2)-PTGER3 axis.
背景：一些microRNA(miRs)已被描述为液体活检和过敏性哮喘的潜在生物标志物，但对miRs在气道表达的治疗作用仍不清楚。
方法：在本研究中，我们在草花粉过敏患者的痰液中研究了miR-相关的表观遗传机制，这些患者接受了或未接受了过敏原特异性免疫治疗(AIT)。使用 miR微阵列和相同样本的全转录组微阵列分析对健康对照(HC)、AIT 治疗和未治疗的草花粉过敏性鼻炎患者(AA)和无哮喘(AR) 的诱导痰样本进行分析。miR靶点在电脑中模拟中被预测，并用于识别逆调控。采用ELISA法检测局部PGE(2)水平。
结果：与HC患者相比，AA患者痰液中有259个miRs上调，只有1个miRs下调。在AIT治疗患者的诱导痰中观察到相反的图像:在哮喘患者AIT治疗后，21个miRs下调，只有4个miRs上调。在这4个miRs中，miR-3935最为突出，因为其预测的靶蛋白PTGER3(前列腺素EP3受体)在治疗AA患者中比未治疗AA患者下调。其配体PGE(2)在过敏性患者，尤其是哮喘患者的痰上清中水平升高，在AIT后下调。最后，局部PGE(2)水平与ILC2频率、痰中IL-13分泌水平、炎症细胞负荷、痰中嗜酸性粒细胞和症状负担相关。
结论：在研究过敏患者的痰液miR表达模式时，我们发现miR-3935与其预测的靶基因前列腺素E-3受体之间存在关联，该基因可能通过抑制PGE(2)-PTGER3轴介导AIT效应。
（中日友好医院呼吸与危重症医学科 李春晓 摘译 林江涛 审校）
（Clin Exp Allergy, 2021.）
（Clin Exp Allergy, 2021.）
Sputum microRNA-screening reveals Prostaglandin EP3 receptor as selective target in allergen-specific immunotherapy
Jakwerth CA, Chaker AM, Guerth F, et al.
Abstract
BACKGROUND: Several microRNAs (miRs) have been described as potential biomarkers in liquid biopsies and in the context of allergic asthma, while therapeutic effects on the airway expression of miRs remain elusive.
METHODS:In this study, we investigated epigenetic miR-associated mechanisms in the sputum of grass pollen-allergic patients with and without allergen-specific immunotherapy (AIT). Induced sputum samples of healthy controls (HC), AIT-treated and untreated grass pollen-allergic rhinitis patients with (AA) and without asthma (AR) were profiled using miR microarray and whole-transcriptome microarray analysis of the same samples. miR targets were predicted in silico and used to identify inverse regulation. Local PGE (2) levels were measured using ELISA.
RESULTS:Two hundred and fifty-nine miRs were upregulated in the sputum of AA patients compared with HC, while only one was downregulated. The inverse picture was observed in induced sputum of AIT-treated patients: while 21 miRs were downregulated, only 4 miRs were upregulated in asthmatics upon AIT. Of these 4 miRs, miR-3935 stood out, as its predicted target PTGER3, the prostaglandin EP3 receptor, was downregulated in treated AA patients compared with untreated. The levels of its ligand PGE(2) in the sputum supernatants of these samples were increased in allergic patients, especially asthmatics, and downregulated after AIT. Finally, local PGE(2) levels correlated with ILC2 frequencies, secreted sputum IL-13 levels, inflammatory cell load, sputum eosinophils and symptom burden.
CONCLUSIONS: While profiling the sputum of allergic patients for novel miR expression patterns, we uncovered an association between miR-3935 and its predicted target gene, the prostaglandin E-3 receptor, which might mediate AIT effects through suppression of the PGE(2)-PTGER3 axis.
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谷氨酰胺缺乏将哮喘状态转变为中性粒细胞气道炎症
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NCR(+)ILC3s 与哮喘严重程度相关的气道微生物组之间的相互作用
