microRNA-23a contributes to asthma by targeting BCL2 in airway epithelial cells and CXCL12 in fibroblasts
microRNA-23a contributes to asthma by targeting BCL2 in airway epithelial cells and CXCL12 in fibroblasts
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microRNA-23a 通过靶向气道上皮细胞中的 BCL2 和成纤维细胞中的 CXCL12 导致哮喘
DOI：
10.1002/jcp.28718
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发表时间：
2019-11-01
影响因子：
5.6
通讯作者：
Lu, Shemin
中科院分区：
文献类型：
--
作者：
Jin, Ai;Bao, Rujuan;Lu, Shemin
炎症过程中气道上皮细胞与上皮下成纤维细胞之间的失调串扰驱动了哮喘的发病机制。生物信息学分析和荧光素酶活性测定表明，B细胞淋巴瘤2（BCL 2）和CXC配体12（CXCL 12）是miR-23 a的潜在靶点。本研究的目的是阐明microRNA-23 a（miR-23 a）对哮喘中BCL 2和CXCL 12的影响。在E3大鼠中，在急性和慢性炎症期间，抗原诱导的肺部炎症后，肺组织中的miR-23 a上调。免疫组织化学显示上皮细胞中的BCL 2以及上皮下成纤维细胞和平滑肌细胞中的CXCL 12下调。用miR-23 a模拟物或抑制剂处理分离的细胞以预期的细胞类型特异性方式改变了BCL 2和CXCL 12的表达。此外，在上皮细胞中，白细胞介素-4上调miR-23 a的表达，从而降低BCL 2的表达，同时增加caspase-3的表达，这是随后的凋亡。在成纤维细胞中，胸腺基质淋巴细胞生成素（TSLP）增加miR-23 a的表达。因此，CXCL 12表达被废除。TSLP通过miR-23 a的作用下调CREB的磷酸化水平。这项研究描述了一种新的机制，其中miR-23 a是哮喘相关气道壁重塑参数的重要细胞类型特异性调节剂。因此，miR-23 a可能成为哮喘治疗的新靶点。
The deregulated cross-talk between airway epithelial cells with subepithelial fibroblasts during inflammation drives the pathogenesis of asthma. Bioinformatics analysis and luciferase activity assay suggested that B cell lymphoma-2 (BCL2) and CXC ligand 12 (CXCL12) are potential targets of miR-23a. The aim of this study was to elucidate the effect of microRNA-23a (miR-23a) on BCL2, and CXCL12 in asthma. In E3 rats, miR-23a was upregulated in lung tissues after antigen-induced pulmonary inflammation during acute and chronic inflammation. Immunohistochemistry showed downregulation of BCL2 in the epithelium and of CXCL12 in subepithelial fibroblasts and smooth muscle cells. Treatment of isolated cells with miR-23a mimic or inhibitor modified the expression of BCL2 and of CXCL12 in the expected cell type-specific manner. Moreover, in epithelial cells, interleukin-4 upregulated miR-23a expression and thereby decreased the expression of BCL2, while increasing the caspase-3 expression, which was followed by apoptosis. In fibroblasts, the expression of miR-23a was increased by thymic stromal lymphopoietin (TSLP). Consequently, the CXCL12 expression was abrogated. The phosphorylation of CREB was also downregulated by TSLP through the action of miR-23a. This study describes a novel mechanism, where miR-23a is an important cell type-specific regulator for asthma-associated airway wall remodeling parameter. Thus, miR-23a may present a potential new target for the therapy of asthma.