Human epididymis protein 4-annexin II binding promotes aberrant epithelial-fibroblast crosstalk in pulmonary fibrosis

Abstract Invasive lung myofibroblasts are the main cause of tissue remodeling in idiopathic pulmonary fibrosis (IPF). A key mechanism contributing to this important feature is aberrant crosstalk between the abnormal/injured lung epithelium and pulmonary fibroblasts. Here, we demonstrate that lungs f...

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Main Authors: Weishuai Zheng, Menglin Zou, Xingxing Hu, Han Gao, Weiwei Song, Qinhui Hou, Yuan Liu, Zhenshun Cheng
Format: Article
Language:English
Published: Nature Portfolio 2025-01-01
Series:Communications Biology
Online Access:https://doi.org/10.1038/s42003-025-07529-7
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author Weishuai Zheng
Menglin Zou
Xingxing Hu
Han Gao
Weiwei Song
Qinhui Hou
Yuan Liu
Zhenshun Cheng
author_facet Weishuai Zheng
Menglin Zou
Xingxing Hu
Han Gao
Weiwei Song
Qinhui Hou
Yuan Liu
Zhenshun Cheng
author_sort Weishuai Zheng
collection DOAJ
description Abstract Invasive lung myofibroblasts are the main cause of tissue remodeling in idiopathic pulmonary fibrosis (IPF). A key mechanism contributing to this important feature is aberrant crosstalk between the abnormal/injured lung epithelium and pulmonary fibroblasts. Here, we demonstrate that lungs from patients with IPF and from mice with bleomycin (BLM)-induced pulmonary fibrosis (PF) are characterized by the induction of human epididymis protein 4 (HE4) overexpression in epithelial cells. HE4 knockdown primarily in epithelial cells attenuates BLM-induced PF in mice, whereas the administration of recombinant mouse HE4 exacerbates fibrosis after BLM stimulation. Mechanistic analysis shows that HE4 and annexin II (ANXA2) specific binding enhances the profibrotic phenotype in epithelial cells, and directly promotes lung fibroblast activation, leading to aberrant epithelial-fibroblast crosstalk and the persistent myofibroblast phenotype. The HE4 and ANXA2 binding site is located after the 30th amino acid at the N terminus of the HE4 molecule. Finally, intratracheal administration of HE4 shRNA lentivirus protects mice against BLM-induced PF. These data suggest that HE4 can serve as a potential therapeutic target in the treatment of IPF.
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issn 2399-3642
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spelling doaj-art-5e21289a252a4864b1cb4ce7723c41db2025-01-26T12:48:05ZengNature PortfolioCommunications Biology2399-36422025-01-018111210.1038/s42003-025-07529-7Human epididymis protein 4-annexin II binding promotes aberrant epithelial-fibroblast crosstalk in pulmonary fibrosisWeishuai Zheng0Menglin Zou1Xingxing Hu2Han Gao3Weiwei Song4Qinhui Hou5Yuan Liu6Zhenshun Cheng7Department of Respiratory and Critical Care Medicine, Zhongnan Hospital of Wuhan UniversityFourth Ward of Medical Care Center, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical UniversityDepartment of Respiratory and Critical Care Medicine, Zhongnan Hospital of Wuhan UniversityDepartment of Respiratory and Critical Care Medicine, Zhongnan Hospital of Wuhan UniversityDepartment of Respiratory and Critical Care Medicine, Zhongnan Hospital of Wuhan UniversityDepartment of Respiratory and Critical Care Medicine, Zhongnan Hospital of Wuhan UniversityDepartment of Respiratory and Critical Care Medicine, Zhongnan Hospital of Wuhan UniversityDepartment of Respiratory and Critical Care Medicine, Zhongnan Hospital of Wuhan UniversityAbstract Invasive lung myofibroblasts are the main cause of tissue remodeling in idiopathic pulmonary fibrosis (IPF). A key mechanism contributing to this important feature is aberrant crosstalk between the abnormal/injured lung epithelium and pulmonary fibroblasts. Here, we demonstrate that lungs from patients with IPF and from mice with bleomycin (BLM)-induced pulmonary fibrosis (PF) are characterized by the induction of human epididymis protein 4 (HE4) overexpression in epithelial cells. HE4 knockdown primarily in epithelial cells attenuates BLM-induced PF in mice, whereas the administration of recombinant mouse HE4 exacerbates fibrosis after BLM stimulation. Mechanistic analysis shows that HE4 and annexin II (ANXA2) specific binding enhances the profibrotic phenotype in epithelial cells, and directly promotes lung fibroblast activation, leading to aberrant epithelial-fibroblast crosstalk and the persistent myofibroblast phenotype. The HE4 and ANXA2 binding site is located after the 30th amino acid at the N terminus of the HE4 molecule. Finally, intratracheal administration of HE4 shRNA lentivirus protects mice against BLM-induced PF. These data suggest that HE4 can serve as a potential therapeutic target in the treatment of IPF.https://doi.org/10.1038/s42003-025-07529-7
spellingShingle Weishuai Zheng
Menglin Zou
Xingxing Hu
Han Gao
Weiwei Song
Qinhui Hou
Yuan Liu
Zhenshun Cheng
Human epididymis protein 4-annexin II binding promotes aberrant epithelial-fibroblast crosstalk in pulmonary fibrosis
Communications Biology
title Human epididymis protein 4-annexin II binding promotes aberrant epithelial-fibroblast crosstalk in pulmonary fibrosis
title_full Human epididymis protein 4-annexin II binding promotes aberrant epithelial-fibroblast crosstalk in pulmonary fibrosis
title_fullStr Human epididymis protein 4-annexin II binding promotes aberrant epithelial-fibroblast crosstalk in pulmonary fibrosis
title_full_unstemmed Human epididymis protein 4-annexin II binding promotes aberrant epithelial-fibroblast crosstalk in pulmonary fibrosis
title_short Human epididymis protein 4-annexin II binding promotes aberrant epithelial-fibroblast crosstalk in pulmonary fibrosis
title_sort human epididymis protein 4 annexin ii binding promotes aberrant epithelial fibroblast crosstalk in pulmonary fibrosis
url https://doi.org/10.1038/s42003-025-07529-7
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