2. Academic Validation
  3. The CCL20-integrin α5β1 interaction enhances TGF-β/Smad signaling to promote fibroblast activation in pulmonary fibrosis

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

  • Nat Commun. 2025 Oct 16;16(1):9183. doi: 10.1038/s41467-025-64211-6.
Suosi Liu # 1,  Qianrong Wang # 1,  Jiali Min # 1 2 3,  Ziying Zhang 1,  Yu Zhang 1,  Jiahui Yang 1,  Yuexin Tan 4,  Lupin Tan 1,  Min Yin 1,  Yan Zhang 1,  Xiangning Tang 1,  Hong Peng 4,  Zhenkun Xia 5,  Yang Xiao 1,  Zhiguang Zhou 1,  Xia Li 6,  Shanshan Liu 7 8 9
Affiliations

Affiliations

  • 1 National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
  • 2 CSU-Sinocare Research Center for Nutrition and Metabolic Health, Xiangya School of Public Health, Central South University, Changsha, Hunan, China.
  • 3 Furong Laboratory, Changsha, China.
  • 4 Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
  • 5 Department of Chestsurgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
  • 6 National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China. [email protected].
  • 7 National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China. [email protected].
  • 8 CSU-Sinocare Research Center for Nutrition and Metabolic Health, Xiangya School of Public Health, Central South University, Changsha, Hunan, China. [email protected].
  • 9 Furong Laboratory, Changsha, China. [email protected].
  • # Contributed equally.
PMID: 41102188 DOI: 10.1038/s41467-025-64211-6
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.

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