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

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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

Edité par CCSD ; eLife Sciences Publication -

International audience. 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.

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