Attenuation of fibroblast activation and fibrosis by adropin in systemic sclerosis

• Published in: Science translational medicine 2024-03, Vol.16 (740), p.eadd6570-eadd6570
• Main Authors: Liang, Minrui, Dickel, Nicholas, Györfi, Andrea-Hermina, SafakTümerdem, Bilgesu, Li, Yi-Nan, Rigau, Aleix Rius, Liang, Chunguang, Hong, Xuezhi, Shen, Lichong, Matei, Alexandru-Emil, Trinh-Minh, Thuong, Tran-Manh, Cuong, Zhou, Xiang, Zehender, Ariella, Kreuter, Alexander, Zou, Hejian, Schett, Georg, Kunz, Meik, Distler, Jörg H W
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Bleomycin; Bleomycin - metabolism; Bleomycin - pharmacology; Cells, Cultured; Disease Models, Animal; Down-regulation; Energy balance; Fibroblasts; Fibroblasts - pathology; Fibrosis; Homeostasis; Humans; Lung diseases; Mice; Nerve Tissue Proteins - metabolism; Receptors, G-Protein-Coupled - metabolism; Receptors, Neurotransmitter - metabolism; Scleroderma; Scleroderma, Systemic - metabolism; Skin - pathology; Systemic sclerosis; Transforming Growth Factor beta - metabolism; Zinc Finger Protein GLI1 - metabolism; Zinc Finger Protein GLI1 - pharmacology
• ISSN: 1946-6234; 1946-6242; 1946-3242
• DOI: 10.1126/scitranslmed.add6570

Fibrotic diseases impose a major socioeconomic challenge on modern societies and have limited treatment options. Adropin, a peptide hormone encoded by the energy homeostasis-associated ( ) gene, is implicated in metabolism and vascular homeostasis, but its role in the pathogenesis of fibrosis remains enigmatic. Here, we used machine learning approaches in combination with functional in vitro and in vivo experiments to characterize adropin as a potential regulator involved in fibroblast activation and tissue fibrosis in systemic sclerosis (SSc). We demonstrated consistent down-regulation of adropin/ in skin across multiple cohorts of patients with SSc. The prototypical profibrotic cytokine TGFβ reduced adropin/ expression in a JNK-dependent manner. Restoration of adropin signaling by therapeutic application of bioactive adropin peptides in turn inhibited TGFβ-induced fibroblast activation and fibrotic tissue remodeling in primary human dermal fibroblasts, three-dimensional full-thickness skin equivalents, mouse models of bleomycin-induced pulmonary fibrosis and sclerodermatous chronic graft-versus-host-disease (sclGvHD), and precision-cut human skin slices. Knockdown of , an adropin receptor, abrogated the antifibrotic effects of adropin in fibroblasts. RNA-seq demonstrated that the antifibrotic effects of adropin were functionally linked to deactivation of GLI1-dependent profibrotic transcriptional networks, which was experimentally confirmed in vitro, in vivo, and ex vivo using cultured human dermal fibroblasts, a sclGvHD mouse model, and precision-cut human skin slices. ChIP-seq confirmed adropin -induced changes in TGFβ/GLI1 signaling. Our study characterizes the TGFβ-induced down-regulation of adropin/ expression as a potential pathomechanism of SSc as a prototypical systemic fibrotic disease that unleashes uncontrolled activation of profibrotic GLI1 signaling.