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 adropin^34–76 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 adropin^34–76 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 adropin^34–76-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.

中文翻译：

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阿德洛平在系统性硬化症中减弱成纤维细胞活化和纤维化

纤维化疾病给现代社会带来了重大的社会经济挑战，并且治疗选择有限。 Adropin 是一种由能量稳态相关 ( ENHO ) 基因编码的肽激素，与新陈代谢和血管稳态有关，但其在纤维化发病机制中的作用仍然是个谜。在这里，我们使用机器学习方法与功能性体外和体内实验相结合，将 adropin 描述为参与系统性硬化症 (SSc) 成纤维细胞激活和组织纤维化的潜在调节剂。我们证明了多组 SSc 患者皮肤中adropin/ ENHO的一致下调。原型促纤维化细胞因子 TGFβ以 JNK 依赖性方式降低 adropin/ ENHO表达。通过生物活性 adropin ^34-76肽的治疗应用恢复 adropin 信号转而抑制 TGFβ 诱导的原代人真皮成纤维细胞、三维全层皮肤等效物、博莱霉素诱导的肺纤维化小鼠模型和纤维化组织重塑。硬皮病慢性移植物抗宿主病（sclGvHD）和精确切割的人体皮肤切片。GPR19 （一种adropin受体）的敲低会消除adropin在成纤维细胞中的抗纤维化作用。 RNA-seq 证明 adropin ^34-76的抗纤维化作用在功能上与 GLI1 依赖性促纤维化转录网络的失活有关，这一点在体外、体内和离体实验中使用培养的人真皮成纤维细胞（一种 sclGvHD 小鼠模型）得到了证实。和精密切割的人体皮肤切片。 ChIP-seq 证实了 adropin ^34-76诱导的 TGFβ/GLI1 信号传导变化。我们的研究将 TGFβ 诱导的 adropin/ ENHO表达下调描述为 SSc 的潜在病理机制，SSc 是一种典型的系统性纤维化疾病，会释放促纤维化 GLI1 信号传导的不受控制的激活。