Identification of Paired-related Homeobox Protein 1 as a key mesenchymal transcription factor in pulmonary fibrosis
| Autor: | Marchal-Duval, Emmeline, Homps-Legrand, Méline, Froidure, Antoine, Jaillet, Madeleine, Ghanem, Mada, Lou, Deneuville, Justet, Aurélien, Maurac, Arnaud, Vadel, Aurelie, Fortas, Emilie, Cazes, Aurelie, Joannes, Audrey, Giersh, Laura, Mal, Herve, Mordant, Pierre, Piolot, Tristan, Truchin, Marin, Mounier, Carine, Schirduan, Ksenija, Korfei, Martina, Gunther, Andreas, Mari, Bernard, Jaschinski, Frank, Crestani, Bruno, Mailleux, Arnaud |
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| Přispěvatelé: | UCL - SSS/IREC/PNEU - Pôle de Pneumologie, ORL et Dermatologie, Physiopathologie et Epidémiologie des Maladies Respiratoires (PHERE (UMR_S_1152 / U1152)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Equipe de recherche sur les relations matrice extracellulaire-cellules (ERRMECe), Fédération INSTITUT DES MATÉRIAUX DE CERGY-PONTOISE (I-MAT), CY Cergy Paris Université (CY)-CY Cergy Paris Université (CY), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Justus-Liebig-Universität Gießen = Justus Liebig University (JLU) |
| Jazyk: | angličtina |
| Rok vydání: | 2023 |
| Předmět: |
MESH: Idiopathic Pulmonary Fibrosis
[SDV.BC]Life Sciences [q-bio]/Cellular Biology lung Mice Transforming Growth Factor beta MESH: Cell Proliferation fibroblasts transcription factors MESH: Homeodomain Proteins cell biology Animals Humans MESH: Animals human MESH: Mice MESH: Transforming Growth Factor beta mouse Cell Proliferation Homeodomain Proteins MESH: Humans fibrosis MESH: Transcription Factors TGF beta pathway Idiopathic Pulmonary Fibrosis Protein Phosphatase 2C MESH: Protein Phosphatase 2C |
| Zdroj: | eLife, Vol. 12, no.1, p. 1-32 (2023) eLife eLife, 2023, 12, pp.e79840. ⟨10.7554/eLife.79840⟩ |
| ISSN: | 2050-084X |
| DOI: | 10.7554/eLife.79840⟩ |
| Popis: | Matrix remodeling is a salient feature of idiopathic pulmonary fibrosis (IPF). Targeting cells driving matrix remodeling could be a promising avenue for IPF treatment. Analysis of transcriptomic database identified the mesenchymal transcription factor PRRX1 as upregulated in IPF. PRRX1, strongly expressed by lung fibroblasts, was regulated by a TGF-β/PGE2 balance in vitro in control and IPF human lung fibroblasts, while IPF fibroblast-derived matrix increased PRRX1 expression in a PDGFR-dependent manner in control ones. PRRX1 inhibition decreased human lung fibroblast proliferation by downregulating the expression of S phase cyclins. PRRX1 inhibition also impacted TGF-β driven myofibroblastic differentiation by inhibiting SMAD2/3 phosphorylation through phosphatase PPM1A upregulation and TGFBR2 downregulation, leading to TGF-β response global decrease. Finally, targeted inhibition of Prrx1 attenuated fibrotic remodeling in vivo with intra-tracheal antisense oligonucleotides in bleomycin mouse model of lung fibrosis and ex vivo using human and mouse precision-cut lung slices. Our results identified PRRX1 as a key mesenchymal transcription factor during lung fibrogenesis. |
| Databáze: | OpenAIRE |
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