Attenuation of fibroblast activation and fibrosis by adropin in systemic sclerosis

Liang M, Dickel N, Györfi AH, SafakTümerdem B, Li YN, Rius Rigau AR, Liang C, Hong X, Shen L, Matei AE, Trinh-Minh T, Tran-Manh C, Zhou X, Zehender A, Kreuter A, Zou H, Schett G, Kunz M, Distler JH (2024)

Publication Language: English

Publication Type: Journal article

Publication year: 2024

Journal

Science Translational Medicine American Association for the Advancement of Science

Book Volume: 16

Journal Issue: 740

DOI: 10.1126/scitranslmed.add6570

Abstract

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 (ENHO) 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/ENHO in skin across multiple cohorts of patients with SSc. The prototypical profibrotic cytokine TGFβ reduced adropin/ENHO expression in a JNK-dependent manner. Restoration of adropin signaling by therapeutic application of bioactive adropin34–76 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 GPR19, an adropin receptor, abrogated the antifibrotic effects of adropin in fibroblasts. RNA-seq demonstrated that the antifibrotic effects of adropin34–76 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 adropin34–76-induced changes in TGFβ/GLI1 signaling. Our study characterizes the TGFβ-induced down-regulation of adropin/ENHO expression as a potential pathomechanism of SSc as a prototypical systemic fibrotic disease that unleashes uncontrolled activation of profibrotic GLI1 signaling.

Authors with CRIS profile

Nicholas Dickel Lehrstuhl für Medizinische Informatik Aleix Rius Rigau Department of Medicine 3 – Rheumatology and Immunology Lichong Shen Professur für Molekulare Mechanismen der Organfibrose Ariella Zehender Department of Medicine 3 – Rheumatology and Immunology Georg Schett Lehrstuhl für Innere Medizin III Meik Kunz Lehrstuhl für Medizinische Informatik

Involved external institutions

Universitätsklinikum Düsseldorf DE Germany (DE) HELIOS Kliniken DE Germany (DE) Fudan University / 复旦大学 CN China (CN)

How to cite

APA:

Liang, M., Dickel, N., Györfi, A.H., SafakTümerdem, B., Li, Y.N., Rius Rigau, A.R.,... Distler, J.H. (2024). Attenuation of fibroblast activation and fibrosis by adropin in systemic sclerosis. Science Translational Medicine, 16(740). https://doi.org/10.1126/scitranslmed.add6570

MLA:

Liang, Minrui, et al. "Attenuation of fibroblast activation and fibrosis by adropin in systemic sclerosis." Science Translational Medicine 16.740 (2024).

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