The Aryl Hydrocarbon Receptor and Its Ligands Inhibit Myofibroblast Formation and Activation

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)-b. The TGF-b 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-b to induce myofibroblast formation, contraction, and proliferation. We found that AHR ligands prevent TGF-b edependent myofibroblast formation, and this ability is dependent on AHR expression. The AHR and AHR ligands block profibrotic Wnt signaling by inhibiting the phosphorylation of GSK3b 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. (Am J Pathol 2016, 186: 3189e3202; http://dx

The Aryl Hydrocarbon Receptor: A Mediator and Potential Therapeutic Target for Ocular and Non-Ocular Neurodegenerative Diseases

“…Ahr −/− EAU mice also display higher protein expression levels of the M1 marker subset, inducible nitric oxide synthase (iNOS) and CD16, and lower protein expression levels of the M2 marker subset, arginase-1 (Arg-1) and CD206, relative to Ahr +/+ EAU mice [129]. Finally, AHR agonists ITE and FICZ have been shown to prevent TGFβ-induced myofibroblast formation in fibroblasts, specifically via inhibiting the β-Catenin/Wnt signaling, leading to the regulation of contractility and proliferation of the human orbital fibroblasts isolated from patients with thyroid eye disease [130]. All in all, though investigating the AHR in the eye is a relatively new area of research, the studies so far indicate that this receptor is involved in modulation of pathogenic pathways, which regulate several retinal diseases (Figure 3) and should be considered as a potential druggable target for the treatment of such maladies.…”

Proton pump inhibitors attenuate myofibroblast formation associated with thyroid eye disease through the aryl hydrocarbon receptor

“…However, it was unclear if this beneficial response was dependent upon the AHR itself, as some ligands have independent functions. More recently, we found that the AHR ligand 6-formylindolo[3,2-b]carbazole (FICZ) is also effective against TGFβ-induced myofibroblast formation and collagen production in TED fibroblasts and normal orbital fibroblasts [9]. Importantly, this study demonstrated for the first time that the AHR pathway is critical in preventing myofibroblast formation in TED patient fibroblasts.…”

“…Importantly, this study demonstrated for the first time that the AHR pathway is critical in preventing myofibroblast formation in TED patient fibroblasts. Further investigation of the mechanism behind FICZ action revealed that the Wnt/β-catenin signaling pathway is critical, and signaling through this pathway was dependent on the AHR [9]. AHR is a ligand-dependent transcription factor with a large binding pocket suggesting there is the opportunity to identify diverse and structurally selective activating ligands [10,11], which could be investigated as potential therapeutics for TED.…”

Negative association between serum aryl hydrocarbon receptor concentrations and β‐cell function in patients with no history of diabetes undergoing coronary angiography

“…Aryl hydrocarbon receptor is widely distributed in the intestine and immune cells, 28,29 and has been implicated in the pathogenesis of inflammation and thyroid eye disease. 30,31 With regard to pancreatic β-cells and insulin secretion, ARNT (a heterodimerization partner for AhR) was reported to play a critical role in maintaining insulin release from pancreatic β-cells. 32 It is not yet clear how AhR is secreted from the cells or what the correlation is between tissue and serum AhR concentrations.…”