title: The Aryl Hydrocarbon Receptor and Its Ligands Inhibit Myofibroblast Formation and Activation: Implications for Thyroid Eye Disease.
abstract: Thyroid eye disease (TED) is a degenerative disease that manifests with detrimental tissue remodeling, myofibroblast accumulation, and scarring in the orbit of affected individuals. Currently, there are no effective therapies for TED that target or prevent the excessive tissue remodeling caused by myofibroblast formation and activation. The canonical cytokine that induces myofibroblast formation is transforming growth factor (TGF)-β. The TGF-β signaling pathway is influenced by aryl hydrocarbon receptor (AHR) signaling pathways. We hypothesized that AHR agonists can prevent myofibroblast formation in fibroblasts from patients with TED, and thus AHR ligands are potential therapeutics for the disease. Orbital fibroblasts explanted from patients with TED were treated with TGF-β to induce myofibroblast formation, contraction, and proliferation. We found that AHR ligands prevent TGF-β-dependent myofibroblast formation, and this ability is dependent on AHR expression. The AHR and AHR ligands block profibrotic Wnt signaling by inhibiting the phosphorylation of GSK3β to prevent myofibroblast formation. These results provide new insight into the molecular pathways underlying orbital scarring in TED. These novel studies highlight the potential of the AHR and AHR ligands as future therapeutic options for eye diseases and possibly also for other scarring conditions.
authors.affiliation: Department of Environmental Medicine, School of Medicine and Dentistry, University of Rochester, Rochester, New York.
authors.forename: Collynn F
authors.initials: CF
authors.lastname: Woeller
authors.affiliation: Flaum Eye Institute, School of Medicine and Dentistry, University of Rochester, Rochester, New York.
authors.forename: Elisa
authors.initials: E
authors.lastname: Roztocil
authors.affiliation: Flaum Eye Institute, School of Medicine and Dentistry, University of Rochester, Rochester, New York.
authors.forename: Christine L
authors.initials: CL
authors.lastname: Hammond
authors.affiliation: Flaum Eye Institute, School of Medicine and Dentistry, University of Rochester, Rochester, New York.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Feldon
authors.affiliation: Department of Environmental Medicine, School of Medicine and Dentistry, University of Rochester, Rochester, New York; Flaum Eye Institute, School of Medicine and Dentistry, University of Rochester, Rochester, New York. Electronic address: richard_phipps@urmc.rochester.edu.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Phipps
mesh_terms: D002478:Cells, Cultured; D005347:Fibroblasts / Q000276:immunology; D055785:Gene Knockdown Techniques; D006111:Graves Disease / Q000276:immunology / Q000503:physiopathology*; D006801:Humans; D008024:Ligands; D058628:Myofibroblasts / Q000276:immunology* / Q000378:metabolism; D009916:Orbital Diseases / Q000276:immunology / Q000503:physiopathology*; D034741:RNA, Small Interfering; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013961:Thyroid Gland / Q000276:immunology / Q000503:physiopathology; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000627:therapeutic use*; D060449:Wnt Signaling Pathway
chemical_list: D008024:Ligands; D034741:RNA, Small Interfering; D018336:Receptors, Aryl Hydrocarbon; D016212:Transforming Growth Factor beta