MERTK inhibition for the treatment of tissue fibrosis [RNA-seq]. MERTK inhibition for the treatment of tissue fibrosis [RNA-seq]

Fibrosis is a core pathway that drives the progression of multiple chronic diseases for which there is a paucity of safe and effective treatments. In these diseases, transforming growth factor–β (TGF-β)–driven scarring propels disease progression. However, targeting this ubiquitously expressed cytokine is unlikely to yield a viable and safe antifibrotic therapy; thus, identification of alternative mechanisms to inhibit TGF-β signalling is required. We identified Mer tyrosine kinase (MERTK) as a TGF-β–inducible nodal effector of fibrosis that is up-regulated with fibrosis in multiple organs in both mice and humans. MERTK also induces TGF-β expression and promotes it’s signalling resulting in a positive feedback loop that promotes fibrosis. Mechanistically, MERTK regulates both canonical and non-canonical TGFβ signalling. Further downstream, MERTK modulates the fibrotic regulatory gene transcription network by regulating chromatin accessibility, RNA polymerase II (pol II) pausing and reprograming the enhancer landscape. Using mouse models of kidney, lung, and liver fibrosis, we demonstrate that this fibrosis-promoting signalling loop can be interrupted by loss of MERTK expression, leading to marked attenuation of fibrosis. Pharmacologic MERTK inhibition reduced fibrosis either when initiated immediately after injury or when initiated after fibrosis is established. Together, this data suggests that MERTK plays a critical role in modulating organ fibrosis, while small-molecule MERTK inhibitors are an attractive target for the treatment of diseases characterized by fibrosis. Overall design: Comparative gene expression profiling analysis of RNA-seq data for WT and Mertk knockout mice liver, kidney tissue of liver, kidney fibrosis models. Comparative gene expression profiling analysis of RNA-seq data for WT and MERTK inhibitor (UNC569) injection mice liver, kidney, and lung tissue of liver, kidney, and lung fibrosis models.

纤维化是驱动多种慢性疾病进展的核心通路，目前针对这类疾病尚缺乏安全有效的治疗手段。在这类疾病中，转化生长因子-β（transforming growth factor-β, TGF-β）介导的瘢痕形成会推动疾病进展。然而，靶向这一广泛表达的细胞因子不太可能获得安全有效的抗纤维化治疗方案，因此亟需探寻抑制TGF-β信号通路的替代机制。我们鉴定出Mer酪氨酸激酶（Mer tyrosine kinase, MERTK）是TGF-β诱导的纤维化核心效应分子，在小鼠和人类的多个器官中，其表达均随纤维化进程而上调。MERTK还可诱导TGF-β的表达并增强其信号通路，进而形成促进纤维化的正反馈环路。从机制上来说，MERTK可同时调控经典与非经典TGF-β信号通路。在更下游的层面，MERTK可通过调控染色质开放性、RNA聚合酶II（RNA polymerase II, pol II）暂停以及重编程增强子景观，来调节纤维化相关调控基因的转录网络。我们利用肾脏、肺脏及肝脏纤维化的小鼠模型开展实验，证实敲除MERTK表达可阻断这一促纤维化信号环路，从而显著减轻纤维化程度。无论是在损伤后即刻给药，还是在纤维化形成后再给药，药物抑制MERTK均可减轻纤维化。综上，本研究数据表明MERTK在调控器官纤维化过程中发挥关键作用，而小分子MERTK抑制剂有望成为治疗纤维化相关性疾病的极具吸引力的治疗靶点。实验整体设计：针对野生型（wild type, WT）与Mertk基因敲除小鼠的肝脏、肾脏组织（来自肝脏、肾脏纤维化模型）进行RNA测序（RNA-seq）数据的比较基因表达谱分析；同时针对野生型小鼠与注射MERTK抑制剂（UNC569）的小鼠的肝脏、肾脏及肺脏组织（来自肝脏、肾脏、肺脏纤维化模型）进行RNA测序（RNA-seq）数据的比较基因表达谱分析。