MERTK inhibition for the treatment of tissue fibrosis [ATAC-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–ß (TGF-ß)–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-ß signalling is required. We identified Mer tyrosine kinase (MERTK) as a TGF-ß–inducible nodal effector of fibrosis that is up-regulated with fibrosis in multiple organs in both mice and humans. MERTK also induces TGF-ß expression and promotes it's signalling resulting in a positive feedback loop that promotes fibrosis. Mechanistically, MERTK regulates both canonical and non-canonical TGFß 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 chromatin accessibility profiling analysis of ATAC-seq data for WT and Mertk knockout mice liver, and kidney tissue of liver, kidney fibrosis models.