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- Title
Inhibition of MERTK reduces organ fibrosis in mouse models of fibrotic disease.
- Authors
Pan, Ziyan; El Sharkway, Rasha; Bayoumi, Ali; Metwally, Mayada; Gloss, Brian S.; Brink, Robert; Lu, David Bo; Liddle, Christopher; Alqahtani, Saleh A.; Yu, Jun; O'Connell, Philip J.; George, Jacob; Eslam, Mohammed
- Abstract
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. Editor's summary: Tissue fibrosis underlies many chronic diseases that are difficult to treat. Transforming growth factor-β (TGFβ) regulates fibrosis, but it is also involved in other processes, making it difficult to target. Pan et al. showed that human fibrotic tissue had increased Mer tyrosine kinase (MERTK), a TGFβ effector. MERTK acted downstream of and in a positive feedback loop with TGFβ in human and mouse cells to promote fibrotic signaling. In mouse models of liver, kidney, and lung fibrosis, genetic deletion of Mertk prevented fibrosis. A pharmacologic inhibitor of MERTK reduced fibrosis in these models and in an additional mouse model of liver fibrosis. These data suggest that fibrosis could be treated by MERTK inhibition. —Brandon Berry
- Subjects
FIBROSIS; LABORATORY mice; RNA polymerase II; ANIMAL disease models; PULMONARY fibrosis; HEPATIC fibrosis; TRANSFORMING growth factors; TRANSCRIPTION factors
- Publication
Science Translational Medicine, 2024, Vol 16, Issue 741, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.adj0133