Identification of Paired-related Homeobox Protein 1 as a key mesenchymal transcription factor in pulmonary fibrosis

Author:

Marchal-Duval Emmeline1,Homps-Legrand Méline1,Froidure Antoine11,Jaillet Madeleine1,Ghanem Mada12,Lou Deneuville12,Justet Aurélien12,Maurac Arnaud1,Vadel Aurelie1,Fortas Emilie1,Cazes Aurelie13,Joannes Audrey14,Giersh Laura1,Mal Herve5,Mordant Pierre16,Piolot Tristan7,Truchin Marin8,Mounier Carine M89,Schirduan Ksenija10,Korfei Martina11,Gunther Andreas11ORCID,Mari Bernard8ORCID,Jaschinski Frank10,Crestani Bruno12,Mailleux Arnaud A1ORCID

Affiliation:

1. Université Paris Cité, Inserm, Physiopathologie et épidémiologie des maladies respiratoires

2. Assistance Publique des Hôpitaux de Paris, Hôpital Bichat, Service de Pneumologie A, FHU APOLLO

3. Assistance Publique des Hôpitaux de Paris, Hôpital Bichat, Département d’Anatomopathologie, FHU APOLLO

4. Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085

5. Assistance Publique des Hôpitaux de Paris, Hôpital Bichat, Service de Pneumologie et Transplantation, FHU APOLLO

6. Assistance Publique des Hôpitaux de Paris, Hôpital Bichat, Service de Chirurgie Thoracique et Vasculaire, FHU APOLLO

7. Plate-forme Orion, CIRB, Collège de France/CNRS-UMR7241/INSERM-U1050, PSL Research University

8. Université Côte d'Azur, CNRS, IPMC, FHU-OncoAge

9. CYU Université, ERRMECe(EA1391)

10. Secarna Pharmaceuticals GmbH & Co. KG

11. Department of Internal Medicine II, University of Giessen-Marburg Lung Center, Justus-Liebig University Giessen

Abstract

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.

Funder

Agence Nationale de la Recherche

European Respiratory Society

Fondation pour la Recherche Médicale

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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