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

Université Paris Cité, Inserm, France
Université Catholique de Louvain, Belgium
Univ Rennes, Inserm, EHESP, France
Assistance Publique - Hôpitaux de Paris, France
Collège de France, CNRS-UMR7241, INSERM-U1050, PSL Research University,, France
Université Côte d'Azur, CNRS, France
Secarna Pharmaceuticals GmbH and Co KG, Germany
University of Giessen, Germany

Jun 1, 2023

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Abstract
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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-b/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.

Data availability

For gene expression profiling, publicly available datasets were obtained from NCBI Gene Expression Omnibus (GSE2052, GSE24206 and GSE21411) , IPF Cell Atlas (www.ipfcellatlas.com) or FibroXplorer (www.fibroXplorer.com). Newly generated expression dataset has been deposited in the Gene Expression Omnibus GSE161364. All data generated or analyzed during this study are included in the manuscript and supporting files.

The following data sets were generated

1. Mari B
2. Mounier C
(2020) Impact of PRRX1 knockdown on the transcriptome of normal human lung fibroblasts (NHLF) in the presence or the absence of TGF-β
NCBI Gene Expression Omnibus, GSE161364.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE161364

The following previously published data sets were used

1. Pardo A
2. Gibson KF
3. Selman M
4. Kaminski N
(2005) IPF versus Control
NCBI Gene Expression Omnibus, GSE2052.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE2052
1. Meltzer E
(2011) Validated Gene Expression Signatures of Idiopathic Pulmonary Fibrosis
NCBI Gene Expression Omnibus, GSE24206.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE24206
1. Cho JH
2. Gelinas R
3. Wang K
4. Etheridge A
5. et al
(2011) Systems biology of interstitial lung diseases
NCBI Gene Expression Omnibus, GSE21411.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE21411

Article and author information

Author details

Emmeline Marchal-Duval

Physiopathologie et épidémiologie des maladies respiratoires, Université Paris Cité, Inserm, Paris, France

Competing interests
No competing interests declared.
Méline Homps-Legrand

Physiopathologie et épidémiologie des maladies respiratoires, Université Paris Cité, Inserm, Paris, France

Competing interests
No competing interests declared.
Antoine Froidure

Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium

Competing interests
Antoine Froidure, received an unrestricted research grant from Boehringer Ingelheim, consulting fees from Boehringer Ingelheim and payment or honoraria from Boehringer Ingelheim and Roche that were paid to their institution. The author has no other competing interests to declare..
Madeleine Jaillet

Physiopathologie et épidémiologie des maladies respiratoires, Université Paris Cité, Inserm, Paris, France

Competing interests
No competing interests declared.
Mada Ghanem

Physiopathologie et épidémiologie des maladies respiratoires, Université Paris Cité, Inserm, Paris, France

Competing interests
No competing interests declared.
Deneuville Lou

Physiopathologie et épidémiologie des maladies respiratoires, Université Paris Cité, Inserm, Paris, France

Competing interests
No competing interests declared.
Aurélien Justet

Physiopathologie et épidémiologie des maladies respiratoires, Université Paris Cité, Inserm, Paris, France

Competing interests
No competing interests declared.
Arnaud Maurac

Physiopathologie et épidémiologie des maladies respiratoires, Université Paris Cité, Inserm, Paris, France

Competing interests
No competing interests declared.
Aurelie Vadel

Physiopathologie et épidémiologie des maladies respiratoires, Université Paris Cité, Inserm, Paris, France

Competing interests
No competing interests declared.
Emilie Fortas

Physiopathologie et épidémiologie des maladies respiratoires, Université Paris Cité, Inserm, Paris, France

Competing interests
No competing interests declared.
Aurelie Cazes

Physiopathologie et épidémiologie des maladies respiratoires, Université Paris Cité, Inserm, Paris, France

Competing interests
No competing interests declared.
Audrey Joannes

Institut de recherche en santé, environnement et travail, Univ Rennes, Inserm, EHESP, Rennes, France

Competing interests
No competing interests declared.
Laura Giersh

Physiopathologie et épidémiologie des maladies respiratoires, Université Paris Cité, Inserm, Paris, France

Competing interests
No competing interests declared.
Herve Mal

Service de Pneumologie et Transplantation, Assistance Publique - Hôpitaux de Paris, Paris, France

Competing interests
No competing interests declared.
Pierre Mordant

Physiopathologie et épidémiologie des maladies respiratoires, Université Paris Cité, Inserm, Paris, France

Competing interests
No competing interests declared.
Tristan Piolot

Collège de France, CNRS-UMR7241, INSERM-U1050, PSL Research University,, Paris, France

Competing interests
No competing interests declared.
Marin Truchin

Université Côte d'Azur, CNRS, Valbonne, France

Competing interests
No competing interests declared.
Carine M Mounier

Université Côte d'Azur, CNRS, Valbonne, France

Competing interests
No competing interests declared.
Ksenija Schirduan

Secarna Pharmaceuticals GmbH and Co KG, Planegg, Germany

Competing interests
Ksenija Schirduan, was a former employee of Secarna Pharmaceuticals..
Martina Korfei

Department of Internal Medicine II, University of Giessen, Gießen, Germany

Competing interests
No competing interests declared.
Andreas Gunther

Department of Internal Medicine, University of Giessen, Gießen, Germany

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-2187-0975
Bernard Mari

Université Côte d'Azur, CNRS, Valbonne, France

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-0422-9182
Frank Jaschinski

Secarna Pharmaceuticals GmbH and Co KG, Planegg, Germany

Competing interests
Frank Jaschinski, is an employee of Secarna Pharmaceuticals..
Bruno Crestani

Service de Pneumologie, Assistance Publique - Hôpitaux de Paris, Paris, France

Competing interests
Bruno Crestani, received grants from Boehringer Ingelheim, received consulting fees, payment or honoraria, and/or support for meetings and/or travel from Apellis, Astra Zeneca, BMS, Boehringer Ingelheim, Novartis, Sanofi. BC also participates on a data safety monitoring board or advisory board for Apellis, BMS, Boehringer Ingelheim, Sanofi and is a member on the Member of the board of trustee of the Fondation du Souffle. The author has no other competing interests to declare..
Arnaud A Mailleux

Physiopathologie et épidémiologie des maladies respiratoires, Université Paris Cité, Inserm, Paris, France

For correspondence
arnaud.mailleux@inserm.fr

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0003-4191-1778

Funding

Agence Nationale de la Recherche (JCJC ANR-16-CE14-00)

Arnaud A Mailleux

European Respiratory Society (ERS-LTRF 2015 - 4476)

Antoine Froidure

Fondation pour la Recherche Médicale (FDT2021060129750)

Méline Homps-Legrand

Fondation pour la Recherche Médicale (FDM41320)

Aurélien Justet

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal experiments were conducted in accordance with the Directive 2010/63/EU of the European Parliament and approved by the local Animal ethics committee ("Comité d'éthique Paris Nord 121", APAFiS #4778 Etudedufacteurdetran_2016031617411315).

Human subjects: The study on human material was performed in accordance with the Declaration of Helsinki and approved by the local ethics committee (CPP Ile de France 1, No.0811760). Written informed consent was obtained from all subjects.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.