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.

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Publication Details

Journal
Nature Communications
Published
2025-10-16
DOI
https://doi.org/10.1038/s41467-025-64211-6
Citations
3
Primary Topic
Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
Type
article
Field-Weighted Citation Impact
4.56

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article

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

Min Yin, Xiangning Tang, Lay Poh Tan, Jiahui Yang et al.
3 citations
Nature Communications
Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
4.56
article

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

Min Yin, Xiangning Tang, Lay Poh Tan, Jiahui Yang, Hong Peng, Suosi Liu, Jiali Min, Zhenkun Xia, Yang Xiao, Qianrong Wang, Shanshan Liu, Zhiguang Zhou, Yu Zhang, Xia Li, Yan Zhang, Ziying Zhang, Yuexin Tan
article en
3 citations

Abstract

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.

Nature CommunicationsVol. 16(1)
Central South University (CN), Second Xiangya Hospital of Central South University (CN), Changsha University of Science and Technology (CN)
National Natural Science Foundation of China, Central South University, Xiamen University
Openalex Percentile: Top 5%
Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
4.56
DOIOpen Access PDFOpenAlex
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