June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Activation of the aryl hydrocarbon receptor inhibits IGF1R and TSHR-mediated signaling in thyroid eye disease
Author Affiliations & Notes
  • Collynn Woeller
    Department of Ophthalmology, University of Rochester Medical Center, Rochester, New York, United States
  • Steven E Feldon
    Department of Ophthalmology, University of Rochester Medical Center, Rochester, New York, United States
  • Elisa Roztocil
    Department of Ophthalmology, University of Rochester Medical Center, Rochester, New York, United States
  • Footnotes
    Commercial Relationships   Collynn Woeller None; Steven Feldon None; Elisa Roztocil None
  • Footnotes
    Support  NIH Grant EY031398 and an unrestricted grant from Research to Prevent Blindness
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 3999 – A0341. doi:
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    • Get Citation

      Collynn Woeller, Steven E Feldon, Elisa Roztocil; Activation of the aryl hydrocarbon receptor inhibits IGF1R and TSHR-mediated signaling in thyroid eye disease. Invest. Ophthalmol. Vis. Sci. 2022;63(7):3999 – A0341.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Thyroid eye disease (TED) is an autoimmune disorder that can lead to proptosis, optic neuropathy and vision loss. In TED, the connective tissue behind the eye becomes inflamed, remodeled and enlarged. Thyroid stimulatory hormone receptor (TSHR) and insulin-like growth factor 1 receptor (IGF1R) signaling are central mediators of TED pathology. Teprotumumab, an IGF1R blocking antibody, recently became the first disease-specific treatment for TED. While teprotumumab represents a major advance and reveals TED specific treatments are feasible, there are limitations with the therapy including: incomplete patient response, patient relapse after therapy, undesirable side effects and cost. Therefore, additional therapies are needed. The objective of this research was to investigate the ability of the aryl hydrocarbon receptor (AHR) to block IGF1R and TSHR signaling in TED orbital fibroblasts.

Methods : Primary human orbital fibroblasts from TED patients and non-TED patients and HEK293FT cells were cultured under standard conditions. HEK293FT cells were transfected with TSHR cDNA and a cyclic-AMP response element (CRE) dependent luciferase reporter construct. Orbital fibroblasts or reporter cells were treated with IGF1, TSH or TED patient specific antibodies in the presence or absence of the AHR activating compounds, FICZ or esomeprazole (a proton pump inhibitor). Cells were collected and analyzed using luciferase reporter assays and quantification of phosphorylation of downstream cell signaling proteins (AKT and CREB). Cell migration was measured using scratch assays in cells treated with or without IGF1.

Results : Activation of TSHR by TSH or TED patient antibodies led to a robust increase in CREB phosphorylation and CREB-dependent luciferase activity in TSHR-expressing reporter cells. Activation of the AHR by FICZ or esomeprazole inhibited TSHR-induced CREB signaling. In TED orbital fibroblasts, IGF1R signaling induced phosphorylation of AKT and increased cell migration. Esomeprazole and FICZ mitigated IGF1-induced AKT phosphorylation and fibroblast migration in a dose-dependent manner.

Conclusions : These data show that activation of the AHR by FICZ or esomeprazole inhibit TSHR and IGF1R signaling. Given that both IGF1R and TSHR pathways are key mediators of TED pathology, these studies reveal that AHR activation may be a novel mechanism to treat TED.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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