Mada Ghanem, Aurélien Justet, Madeleine Jaillet, Eirini Vasarmidi, Tiara Boghanim, Mouna Hachem, Aurelie Vadel, Audrey Joannes, Pierre Mordant, Agshin Balayev, Taylor Adams, Hervé Mal, Aurélie Cazes, Nicolas Poté, Arnaud Mailleux, Bruno Crestani
{"title":"Identification of FGFR4 as a regulator of myofibroblast differentiation in Pulmonary Fibrosis.","authors":"Mada Ghanem, Aurélien Justet, Madeleine Jaillet, Eirini Vasarmidi, Tiara Boghanim, Mouna Hachem, Aurelie Vadel, Audrey Joannes, Pierre Mordant, Agshin Balayev, Taylor Adams, Hervé Mal, Aurélie Cazes, Nicolas Poté, Arnaud Mailleux, Bruno Crestani","doi":"10.1152/ajplung.00184.2023","DOIUrl":null,"url":null,"abstract":"<p><p>Introduction IPF is a devastating lung disease with limited therapeutic options. FGFR4 is a known receptor for several paracrine Fibroblast growth factors (FGFs). FGFR4 is also the main receptor for FGF19, an endocrine FGF that was demonstrated by our group to have anti-fibrotic properties in the lung. We aimed to determine whether FGFR4 could modulate pulmonary fibrogenesis. Methods We assessed FGFR4 mRNA and protein levels in IPF and control lungs. In vitro, we determined the effect of TGF-b, Endothelin-1 and PDGF on FGFR4 expression in human lung fibroblasts. We determined the effect FGFR4 inhibition, using a specific pharmacological inhibitor (FGF401), or genetic deletion in murine embryonic fibroblasts (MEFs) on TGF-b-induced myofibroblastic differentiation. In vivo, we evaluated the development of bleomycin-induced lung fibrosis in <i>Fgfr4</i>-deficient (<i>Fgfr4</i>-/-) mice compared to Wild Type littermates (WT), and after FGF401 treatment in WT mice compared to a control group receiving the solvent only. Results FGFR4 was decreased in IPF lungs as compared to control lungs, at mRNA and protein levels. In vitro, FGFR4 was downregulated after treatment by TGF- β, Endothelin-1 and PDGF. In vitro, FGFR4 inhibition by FGF401 prevented TGF-b1-induced collagen and ACTA2 increase in lung fibroblasts. Similar results were observed in <i>Fgfr4</i>-/- MEFs. In vivo, FGFR4 genetic deficiency or FGFR4 pharmacological inhibition did not modulate bleomycin-induced pulmonary fibrosis. Conclusion Our data suggest that FGFR4 exerts pro-fibrotic properties by enhancing TGF- β signaling in vitro. However, the inhibition of FGFR4 is not sufficient to prevent the development of pulmonary fibrosis in vivo.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":null,"pages":null},"PeriodicalIF":3.6000,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"American journal of physiology. Lung cellular and molecular physiology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1152/ajplung.00184.2023","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHYSIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Introduction IPF is a devastating lung disease with limited therapeutic options. FGFR4 is a known receptor for several paracrine Fibroblast growth factors (FGFs). FGFR4 is also the main receptor for FGF19, an endocrine FGF that was demonstrated by our group to have anti-fibrotic properties in the lung. We aimed to determine whether FGFR4 could modulate pulmonary fibrogenesis. Methods We assessed FGFR4 mRNA and protein levels in IPF and control lungs. In vitro, we determined the effect of TGF-b, Endothelin-1 and PDGF on FGFR4 expression in human lung fibroblasts. We determined the effect FGFR4 inhibition, using a specific pharmacological inhibitor (FGF401), or genetic deletion in murine embryonic fibroblasts (MEFs) on TGF-b-induced myofibroblastic differentiation. In vivo, we evaluated the development of bleomycin-induced lung fibrosis in Fgfr4-deficient (Fgfr4-/-) mice compared to Wild Type littermates (WT), and after FGF401 treatment in WT mice compared to a control group receiving the solvent only. Results FGFR4 was decreased in IPF lungs as compared to control lungs, at mRNA and protein levels. In vitro, FGFR4 was downregulated after treatment by TGF- β, Endothelin-1 and PDGF. In vitro, FGFR4 inhibition by FGF401 prevented TGF-b1-induced collagen and ACTA2 increase in lung fibroblasts. Similar results were observed in Fgfr4-/- MEFs. In vivo, FGFR4 genetic deficiency or FGFR4 pharmacological inhibition did not modulate bleomycin-induced pulmonary fibrosis. Conclusion Our data suggest that FGFR4 exerts pro-fibrotic properties by enhancing TGF- β signaling in vitro. However, the inhibition of FGFR4 is not sufficient to prevent the development of pulmonary fibrosis in vivo.
期刊介绍:
The American Journal of Physiology-Lung Cellular and Molecular Physiology publishes original research covering the broad scope of molecular, cellular, and integrative aspects of normal and abnormal function of cells and components of the respiratory system. Areas of interest include conducting airways, pulmonary circulation, lung endothelial and epithelial cells, the pleura, neuroendocrine and immunologic cells in the lung, neural cells involved in control of breathing, and cells of the diaphragm and thoracic muscles. The processes to be covered in the Journal include gas-exchange, metabolic control at the cellular level, intracellular signaling, gene expression, genomics, macromolecules and their turnover, cell-cell and cell-matrix interactions, cell motility, secretory mechanisms, membrane function, surfactant, matrix components, mucus and lining materials, lung defenses, macrophage function, transport of salt, water and protein, development and differentiation of the respiratory system, and response to the environment.