Decreased epithelial and sputum miR-221-3p associates with airway eosinophilic inflammation and CXCL17 expression in asthma
Decreased epithelial and sputum miR-221-3p associates with airway eosinophilic inflammation and CXCL17 expression in asthma
复制标题
上皮和痰中 miR-221-3p 的减少与哮喘中气道嗜酸性粒细胞炎症和 CXCL17 表达相关。
DOI：
10.1152/ajplung.00567.2017
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发表时间：
2018-08-01
影响因子：
4.9
通讯作者：
Zhen, Guohua
中科院分区：
文献类型：
--
作者：
Zhang, Kan;Liang, Yuxia;Zhen, Guohua
气道嗜酸性粒细胞炎症是2型高哮喘的一个关键特征。上皮microRNA（miR）在气道嗜酸性粒细胞炎症中的作用尚不清楚。我们通过定量PCR检测了77例有症状的、近期确诊的、未接受过激素治疗的哮喘受试者和36例健康对照者的支气管刷检物、诱导痰和血浆中miR-221- 3 p的表达，并分析了miR-221- 3 p表达与气道嗜酸性粒细胞增多之间的相关性。我们发现，上皮，痰液和血浆中的miR-221- 3 p表达在哮喘患者中显著降低。上皮细胞miR-221- 3 p与诱导痰和支气管活检中的嗜酸性粒细胞、呼出的一氧化氮分数、血嗜酸性粒细胞、2型状态的上皮细胞基因特征以及引起哮喘受试者第一秒用力呼气量下降20%所需的乙酰甲胆碱激发剂量相关。痰液miR-221- 3 p也与气道嗜酸性粒细胞增多相关，并在吸入皮质类固醇治疗后部分恢复。抑制miR-221- 3 p表达可抑制BEAS-2B支气管上皮细胞中趋化因子（C-C基序）配体（CCL）24（嗜酸性粒细胞趋化因子-2）、CCL 26（嗜酸性粒细胞趋化因子-3）和骨膜蛋白（POT 3）的表达。我们证实了趋化因子（C-X-C基序）配体（CXCL）17，一种抗炎趋化因子，是miR-221- 3 p的靶点，并且上皮CXCL 17表达在哮喘中显著增加。CXCL 17通过p38 MAPK途径抑制CCL 24、CCL 26和POCL 4的表达。在室内尘螨攻击的小鼠中，气道中miR-221- 3 p的过表达加重了气道嗜酸性粒细胞炎症，抑制了CXCL 17的表达，并增强了CCL 24、CCL 26和POCL 17的表达。总之，上皮和痰miR-221- 3 p是哮喘气道嗜酸性粒细胞炎症的新生物标志物。上皮miR-221- 3 p减少可能通过上调抗炎趋化因子CXCL 17来保护气道嗜酸性粒细胞炎症。
Airway eosinophilic inflammation is a key feature of type 2 high asthma. The role of epithelial microRNA (miR) in airway eosinophilic inflammation remains unclear. We examined the expression of miR-221-3p in bronchial brushings, induced sputum, and plasma from 77 symptomatic, recently diagnosed, steroid-naive subjects with asthma and 36 healthy controls by quantitative PCR and analyzed the correlation between miR-221-3p expression and airway eosinophilia. We found that epithelial, sputum, and plasma miR-221-3p expression was significantly decreased in subjects with asthma. Epithelial miR-221-3p correlated with eosinophil in induced sputum and bronchial biopsies, fraction of exhaled nitric oxide, blood eosinophil, epithelial gene signature of type 2 status, and methacholine provocative dosage required to cause a 20% decline in forced expiratory volume in the first second in subjects with asthma. Sputum miR-221-3p also correlated with airway eosinophilia and was partially restored after inhaled corticosteroid treatment. Inhibition of miR-221-3p expression suppressed chemokine (C-C motif) ligand (CCL) 24 (eotaxin-2), CCL26 (eotaxin-3), and periostin (POSTN) expression in BEAS-2B bronchial epithelial cells. We verified that chemokine (C-X-C motif) ligand (CXCL) 17, an anti-inflammatory chemokine, is a target of miR-221-3p, and epithelial CXCL17 expression significantly increased in asthma. CXCL17 inhibited CCL24, CCL26, and POSTN expression via the p38 MAPK pathway. Airway overexpression of miR-221-3p exacerbated airway eosinophilic inflammation, suppressed CXCL17 expression, and enhanced CCL24, CCL26, and POSTN expression in house dust mite-challenged mice. Taken together, epithelial and sputum miR-221-3p are novel biomarkers for airway eosinophilic inflammation in asthma. Decreased epithelial miR-221-3p may protect against airway eosinophilic inflammation by upregulating anti-inflammatory chemokine CXCL17.