Profiling of healthy and asthmatic airway smooth muscle cells following interleukin-1β treatment: a novel role for CCL20 in chronic mucus hypersecretion
Profiling of healthy and asthmatic airway smooth muscle cells following interleukin-1β treatment: a novel role for CCL20 in chronic mucus hypersecretion
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DOI：
10.1183/13993003.00310-2018
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发表时间：
2018-08-01
影响因子：
24.3
通讯作者：
Burgess, Janette K.
中科院分区：
文献类型：
--
作者：
Faiz, Alen;Weckmann, Markus;Burgess, Janette K.
慢性粘液分泌过多（CMH）导致哮喘的发病率和死亡率，并且在患有严重的类固醇耐药疾病的患者亚组中仍然不受当前治疗的控制。气道上皮细胞和气道平滑肌细胞（ASMC）之间的串扰改变，由促炎细胞因子如白细胞介素（IL）-1 β驱动，提供了一种影响CMH的潜在机制。本研究通过比较IL-1 β诱导的哮喘和对照来源的ASMCs的基因表达谱以及随后的旁分泌对气道上皮粘液分泌的影响来研究CMH的潜在机制。用鉴定的候选物处理气液界面（AM培养的CALU-3和原代气道上皮细胞，并评估粘液产生。与轻度哮喘患者和健康对照相比，在中度哮喘患者和健康对照中，IL-1 β诱导的CCL 20表达和蛋白释放增加。与对照相比，IL-10诱导哮喘来源的ASMCs中MIR 146 A表达降低。降低MIR 146 A的表达在16名哮喘患者与39名健康供体的支气管活检中得到体内验证。miR-146 a-5 p过表达废除了ASMCs中CCL 20的释放。CCL 20处理ALI培养的CALU-3和原代气道上皮细胞诱导粘液产生，而痰液中CCL 20水平与哮喘患者CMH水平升高相关。ASMCs产生的CCL 20升高可能是由于miR-146 a-5 p表达失调所致，可能有助于哮喘中粘液产生的增加。
Chronic mucus hypersecretion (CMH) contributes to the morbidity and mortality of asthma, and remains uncontrolled by current therapies in the subset of patients with severe, steroidresistant disease. Altered cross-talk between airway epithelium and airway smooth muscle cells (ASMCs), driven by pro-inflammatory cytokines such as interleukin (IL)-1 beta, provides a potential mechanism that influences CMH. This study investigated mechanisms underlying CMH by comparing IL-1 beta-induced gene expression profiles between asthma and control-derived ASMCs and the subsequent paracrine influence on airway epithelial mucus production in vitro.IL-1 beta-treated ASMCs from asthmatic patients and healthy donors were profiled using microarray analysis and ELISA. Air liquid interface (AM-cultured CALU-3 and primary airway epithelial cells were treated with identified candidates and mucus production assessed.The IL-1 beta-induced CCL20 expression and protein release was increased in ASMCs from moderate compared with mild asthmatic patients and healthy controls. 1L-10 induced lower MIR146A expression in asthma-derived ASMCs compared with controls. Decreased MIR146A expression was validated in vivo in bronchial biopsies from 16 asthmatic patients versus 39 healthy donors. miR-146a-5p overexpression abrogated CCL20 release in ASMCs. CCL20 treatment of ALI-cultured CALU-3 and primary airway epithelial cells induced mucus production, while CCL20 levels in sputum were associated with increased levels of CMH in asthmatic patients.Elevated CCL20 production by ASMCs, possibly resulting from dysregulated expression of the antiinflammatory miR-146a-5p, may contribute to enhanced mucus production in asthma.