MUC4 is overexpressed in idiopathic pulmonary fibrosis and collaborates with transforming growth factor β inducing fibrotic responses

• Published in: Mucosal immunology Vol. 14; no. 2; pp. 377 - 388
• Main Authors: Milara, Javier, Ballester, Beatriz, Safont, M.J., Artigues, Enrique, Escrivá, Juan, Morcillo, Esteban, Cortijo, Julio
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.03.2021; Nature Publishing Group US; Elsevier Limited
• Subjects: A549 Cells; Allergology; Alveoli; Antibodies; Biomedical and Life Sciences; Biomedicine; Bleomycin; Cell membranes; Cell proliferation; Cellular Senescence; Epithelial cells; Fibroblasts; Fibroblasts - pathology; Fibrosis; Gastroenterology; Gene Expression Regulation, Neoplastic; Gene silencing; Humans; Idiopathic Pulmonary Fibrosis - immunology; Idiopathic Pulmonary Fibrosis - metabolism; Immunofluorescence; Immunology; Immunoprecipitation; Lung - pathology; Lung diseases; Mesenchyme; Molecular Targeted Therapy; MUC4 gene; Mucin; Mucin-4 - genetics; Mucin-4 - metabolism; Phosphorylation; Pulmonary arteries; Pulmonary artery; Pulmonary fibrosis; Respiratory Mucosa - metabolism; Respiratory Mucosa - pathology; RNA, Small Interfering - genetics; Senescence; Signal Transduction; siRNA; Smad protein; Smad3 protein; Smad3 Protein - metabolism; Transforming Growth Factor beta - metabolism; Transforming growth factor-b; Transforming growth factor-b1; Up-Regulation
• ISSN: 1933-0219; 1935-3456; 1935-3456
• DOI: 10.1038/s41385-020-00343-w

Several mucins are implicated in idiopathic pulmonary fibrosis (IPF); however, there is no evidence regarding the role of MUC4 in the development of IPF. Here we demonstrated that MUC4 was overexpressed in IPF patients (n = 22) compared with healthy subjects (n = 21) and located in pulmonary arteries, bronchial epithelial cells, fibroblasts, and hyperplastic alveolar type II cells. Decreased expression of MUC4 using siRNA–MUC4 inhibited the mesenchymal/myofibroblast transformations of alveolar type II A549 cells and lung fibroblasts, as well as cell senescence and fibroblast proliferation induced by TGF-β1. The induction of the overexpression of MUC4 increased the effects of TGF-β1 on mesenchymal/myofibroblast transformations and cell senescence. MUC4 overexpression and siRNA–MUC4 gene silencing increased or decreased, respectively, the phosphorylation of TGFβRI and SMAD3, contributing to smad-binding element activation. Immunoprecipitation analysis and confocal immunofluorescence showed the formation of a protein complex between MUC4β/p-TGFβRI and p-SMAD3 in the cell membrane after TGF-β1 stimulation and in lung tissue from IPF patients. Bleomycin-induced lung fibrosis was reduced in mice transiently transfected with siRNA–MUC4. This study shows that MUC4 expression is enhanced in IPF and promotes fibrotic processes in collaboration with TGF-β1 canonical pathway that could be an attractive druggable target for human IPF.