The CCL20–integrin α5β1 interaction enhances TGF-β/Smad signaling to promote fibroblast activation in pulmonary fibrosis

Limited therapeutic options are available for pulmonary fibrosis because its molecular pathogenesis remains unclear. Here, we find that chemokine CCL20 expression is increased in both murine models and patients with pulmonary fibrosis. Type 2 alveolar epithelial cells are identified as the major producers of CCL20, and increased CCL20 expression results from decreased expression of the transcription factor JUN. AEC2-specific deletion of CCL20 protects mice from bleomycin-induced pulmonary fibrosis. Mechanistic studies reveal that CCL20 interacts with integrin α5β1, but not the classical receptor CCR6, on fibroblasts and subsequently enhances TGF-β/Smad signaling, which promotes the differentiation of lung fibroblasts into myofibroblasts. Antibody blockade of CCL20 or disruption of the CCL20–integrin α5β1 interaction attenuates established pulmonary fibrosis. Overall, our study highlights the CCL20–integrin α5β1–TGF-β signaling cascade as a potential therapeutic target for pulmonary fibrosis.