Abstract
Epithelial-mesenchymal transition (EMT) is essential in asthma airway remodeling. IL-33 from epithelial cells is involved in pulmonary fibrosis. CD146 has been extensively explored in cancer-associated EMT. Whether IL-33 regulates CD146 in the EMT process associated with asthma airway remodeling is still largely unknown. We hypothesized that EMT in airway remodeling was regulated by the IL-33/CD146 axis. House dust mite (HDM) extract increased the expression of IL-33 and CD146 in epithelial cells. Increased expression of CD146 in HDM-treated epithelial cells could be blocked with an ST2-neutralizing antibody. Moreover, HDM-induced EMT was dependent on the CD146 and TGF-β/SMAD-3 signaling pathways. IL-33 deficiency decreased CD146 expression and alleviated asthma severity. Similarly, CD146 deficiency mitigated EMT and airway remodeling in a murine model of chronic allergic airway inflammation. Furthermore, CD146 expression was significantly elevated in asthma patients. We concluded that IL-33 from HDM extract-treated alveolar epithelial cells stimulated CD146 expression, promoting EMT in airway remodeling in chronic allergic inflammation.
Highlights
Asthma is a disease that is characterized by airway inflammation, airway remodeling, and airway hyperresponsiveness [1]
We first demonstrated that House dust mite (HDM) extract promoted CD146 expression in alveolar epithelial cells via IL33, and this effect was blocked with an antibody against the IL-33 receptor ST2
CD146, which was upregulated with an expression plasmid or downregulated with an siRNA plasmid, was found to play essential roles in E-cadherin expression in alveolar epithelial cells, suggesting that CD146 may mediate Epithelial-mesenchymal transition (EMT) in asthma
Summary
Asthma is a disease that is characterized by airway inflammation, airway remodeling, and airway hyperresponsiveness [1]. Epithelial-mesenchymal transition (EMT) is a pathophysiological process induced by multiple signaling pathways centered on TGF-β and refers to the loss of function of epithelial cells and their transformation to mesenchymal cells, including a decrease in E-cadherin, and an increase in N-cadherin expression [3,4,5]. An increasing number of studies have demonstrated that increased EMT plays an important role in airway remodeling in asthma [5, 6]. As a multifunctional molecule [7], CD146 plays diverse biological roles in tumors, atherosclerosis, systemic sclerosis, and other diseases [8,9,10]. CD146 is associated with pulmonary infections, in which it promotes the adherence of bacteria or viruses to airway epithelial cells [11,12,13,14].
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