| Autor: |
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. |
| Předmět: |
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| Zdroj: |
Science Translational Medicine; 3/27/2024, Vol. 17 Issue 740, p1-15, 15p |
| Abstrakt: |
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. Editor's summary: Systemic sclerosis (SSc) usually presents with fibrosis of the skin, although other organs can also be affected. At present, there is no cure for this disease. Liang et al. identify the peptide hormone adropin as a repressor of fibroblast activation and show that its activity is often dysregulated in patients with SSc, likely because of increased TGFβ activity. Adropin-derived peptides repressed pathogenic TGFβ signaling, reduced fibroblast activation, and showed antifibrotic activity in mouse models of skin and lung fibrosis as well as in human skin biopsies. These findings position adropin as a therapeutic target in tissue fibrosis. —Catherine Charneski [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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