Transforming growth factor–β (TGFβ) drives fibrosis and disease progression in a number of chronic disorders, but targeting this ubiquitously expressed cytokine may not yield a viable and safe antifibrotic therapy. Here, we sought to identify alternative ways to inhibit TGFβ signaling using human hepatic stellate cells and macrophages from humans and mice in vitro, as well as mouse models of liver, kidney, and lung fibrosis. We identified Mer tyrosine kinase (MERTK) as a TGFβ-inducible effector of fibrosis that was up-regulated during fibrosis in multiple organs in three mouse models. We confirmed these findings in liver biopsy samples from patients with metabolic dysfunction-associated fatty liver disease (MAFLD). MERTK also induced TGFβ expression and drove TGFβ signaling resulting in a positive feedback loop that promoted fibrosis in cultured cells. MERTK regulated both canonical and noncanonical TGFβ signaling in both mouse and human cells in vitro. MERTK increased transcription of genes regulating fibrosis by modulating chromatin accessibility and RNA polymerase II activity. In each of the three mouse models, disrupting the fibrosis-promoting signaling loop by reducing MERTK expression reduced organ fibrosis. Pharmacological inhibition of MERTK reduced fibrosis in these mouse models either when initiated immediately after injury or when initiated after fibrosis was established. Together, these data suggest that MERTK plays a role in modulating organ fibrosis and may be a potential target for treating fibrotic diseases.

中文翻译：

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抑制 MERTK 可减少纤维化疾病小鼠模型中的器官纤维化

转化生长因子-β (TGFβ) 可驱动许多慢性疾病的纤维化和疾病进展，但针对这种普遍表达的细胞因子可能无法产生可行且安全的抗纤维化治疗。在这里，我们试图在体外使用人肝星状细胞和来自人和小鼠的巨噬细胞以及肝、肾和肺纤维化的小鼠模型来寻找抑制 TGFβ 信号传导的替代方法。我们发现 Mer 酪氨酸激酶 (MERTK) 是一种 TGFβ 诱导的纤维化效应物，在三种小鼠模型的多个器官纤维化过程中表达上调。我们在代谢功能障碍相关脂肪肝病 (MAFLD) 患者的肝活检样本中证实了这些发现。 MERTK 还诱导 TGFβ 表达并驱动 TGFβ 信号传导，形成正反馈循环，促进培养细胞纤维化。 MERTK 在体外调节小鼠和人类细胞中的经典和非经典 TGFβ 信号传导。 MERTK 通过调节染色质可及性和 RNA 聚合酶 II 活性来增加调节纤维化的基因转录。在三种小鼠模型中，通过减少 MERTK 表达来破坏促进纤维化的信号环路，可减少器官纤维化。 MERTK 的药理抑制可减少这些小鼠模型中的纤维化，无论是在损伤后立即开始还是在纤维化建立后开始。总之，这些数据表明 MERTK 在调节器官纤维化中发挥作用，并且可能是治疗纤维化疾病的潜在靶点。