Profiling of healthy and asthmatic airway smooth muscle cells following interleukin-1β treatment: a novel role for CCL20 in chronic mucus hypersecretion

Chronic mucus hyper-secretion (CMH) contributes to the morbidity and mortality of asthma and remains uncontrolled by current therapies in the subset of patients with severe, steroid resistant disease. Altered cross-talk between airway epithelium and airway smooth muscle cells (ASMCs), driven by pro-inflammatory cytokines such as IL-1β, provides a potential mechanism that influences CMH. This study investigated mechanisms underlying CMH by comparing IL-1β-induced gene expression profiles between asthma and control-derived ASMCs and the subsequent paracrine influence on airway epithelial mucus production in-vitro . IL-1β-treated ASMCs from asthmatic and healthy donors were profiled using microarray analysis and ELISA. Air-liquid interface (ALI)-cultured CALU-3 and primary airway epithelial cells were treated with identified candidates and mucus production assessed. The IL-1β-induced CCL20 expression and protein release was increased in ASMCs from moderate compared to mild asthmatics and healthy controls . IL-1β induced lower MIR146A expression in asthma-derived ASMCs compared to controls. Decreased MIR146A expression was validated in-vivo in bronchial biopsies from 16 asthmatic 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 ASMC, possibly resulting from dysregulated expression of the anti-inflammatory miR-146a-5p, may contribute to enhanced mucus production in asthma.