Interleukin-17A Promotes Airway Remodeling in Chronic Obstructive Pulmonary Disease by Activating C-X-C Motif Chemokine Ligand 12 Secreted by Lung Fibroblasts

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Background: The interactions between fibroblasts and bronchial epithelial cells play important roles in the development of chronic obstructive pulmonary disease (COPD). Interleukin (IL)-17A triggers the activation of fibroblasts and the secretion of inflammatory mediators, which promotes epithelial-mesenchymal transition (EMT) in bronchial epithelial cells. Fibroblasts secrete C-X-C motif chemokine ligand 12 (CXCL12), which specifically binds to its receptor, C-X-C motif chemokine receptor 4 (CXCR4) to mediate inflammatory responses. This study aims to investigate IL-17A- and CXCL12-induced airway remodeling. Methods: -value < 0.05 was considered statistically significant. Results: Through in vitro experiments, we found that IL-17A-activated primary lung fibroblasts secreted CXCL12 and stimulated EMT in bronchial epithelial cells. However, these effects could be blocked by neutralizing IL-17A or CXCL12. In vivo, an anti-IL-17A antibody or a CXCR4 antagonist could reverse the degree of EMT in the lungs of the COPD mouse model. The IL-17A-induced EMT and increased CXCL12 expression occurred via extracellular signal-regulated kinase (ERK)/phosphorylated-ERK pathways. Conclusion: This study showed that exposure of mice to CS and IL-17A stimulation upregulated CXCL12 expression and induced EMT by activating the ERK signaling pathway. These data offer a novel perspective regarding the molecular mechanism of CXCL12/CXCR4 signaling in IL-17A-induced EMT related to airway remodeling.