Inhibition of MERTK reduces organ fibrosis in mouse models of fibrotic disease.

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.

• Authors: Ziyan Pan, Rasha El Sharkway, Ali Bayoumi, Mayada Metwally, Brian S Gloss, Robert Brink, David Bo Lu, Christopher Liddle, Saleh A Alqahtani, Jun Yu, Philip J O'Connell, Jacob George, Mohammed Eslam
• Journal: Science translational medicine (Sci Transl Med) Vol. 16 Issue 741 Pg. eadj0133 (Apr 03 2024) ISSN: 1946-6242 [Electronic] United States
• PMID: 38569018 (Publication Type: Journal Article)

Chemical References

• c-Mer Tyrosine Kinase
• MERTK protein, human
• Protein-Tyrosine Kinases
• Transforming Growth Factor beta
• Mertk protein, mouse

Topics

• Animals
• Humans
• Mice
• c-Mer Tyrosine Kinase (metabolism)
• Disease Models, Animal
• Fibrosis
• Liver (metabolism)
• Protein-Tyrosine Kinases (metabolism)
• Transforming Growth Factor beta (metabolism)