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.
Competing Interests: EM, MH, MJ, MG, DL, AJ, AM, AV, EF, AC, AJ, LG, HM, PM, TP, MT, CM, MK, AG, BM, AM No competing interests declared, AF 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, KS was a former employee of Secarna Pharmaceuticals, FJ is an employee of Secarna Pharmaceuticals, BC 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
(© 2023, Marchal-Duval, Homps-Legrand et al.)