GLCCI1 alleviates airway remodeling in asthmatic mice by inhibiting ZEB1-mediated epithelial-mesenchymal transition

Asthma is a heterogeneous disease characterized by chronic airway inflammation and airway hyperresponsiveness. Our previous study found that glucocorticoid-induced transcript 1 (GLCCI1) is down-regulated in the lung tissues of asthmatic mice. This work attempted to determine the precise mechanism of GLCCI1 in asthma. The asthma mouse model was constructed by administration of ovalbumin (OVA). OVA challenge elevated airway resistance and increased the levels of inflammatory factors (IL-1β, TNF-α, IL-13, TGF-β, IL-4, and IL-5) in the asthmatic mice. Histological analysis revealed enhanced inflammation and collagen deposition in lung tissues of asthmatic mice. GLCCI1 overexpression reduced airway resistance, lung inflammation, and fibrosis in asthmatic mice. In vitro, airway epithelial cells (BEAS-2B) were treated with TNF-α to mimic the condition of asthma. GLCCI1 overexpression enhanced the phosphorylation of PI3K, AKT, and mTOR, thereby activating the PI3K/AKT/mTOR signaling pathway in asthmatic mice and TNF-α-treated BEAS-2B. GLCCI1 up-regulation inhibited the expression of ZEB1, N-cadherin, Vimentin and elevated E-cadherin in asthmatic mice and TNF-α-treated BEAS-2B. The influence conferred by GLCCI1 overexpression was reversed by ZEB1 upregulation. It indicated that GLCCI1 suppressed ZEB1-mediated epithelial-mesenchymal transition (EMT). Both LY294002 (PI3K inhibitor) and Rapamycin (mTOR inhibitor) treatment reversed GLCCI1 overexpression-induced inhibition of ZEB1-mediated EMT in TNF-α-treated BEAS-2B. In summary, this work demonstrated that GLCCI1 overexpression inhibits ZEB1-mediated epithelial-mesenchymal transition by activating PI3K/AKT/mTOR signaling pathway, thereby alleviating airway remodeling in asthmatic mice. Thus, this study suggests that GLCCI1 may be a potential target for asthma treatment.