Abstract
Purpose :
In Thyroid Eye Disease (TED), the connective tissue behind the eye becomes inflamed and enlarged. As orbital tissue expands, patients develop proptosis, diplopia, optic neuropathy and in severe cases, blindness. Cigarette smoking increases the chances of developing TED by more than 7-fold. Currently, there is no cure for TED and targeted treatments are limited. The insulin-like growth factor 1 receptor (IGF1R) and the aryl hydrocarbon receptor (AHR) pathways are implicated in inflammation and TED tissue remodeling. The goal of this work is to better define these pathways so that novel therapeutics can be identified.
Methods :
Orbital fibroblasts (OFs) were treated with the IGF1 with or without cigarette smoke extract. The endogenous AHR ligand FICZ was used to activate AHR in OFs. IGF1R expression was depleted by IGF1R specific siRNA. AHR knockout OFs were generated using CRISPR/Cas9n. Cell proliferation was measured by BrdU incorporation and inflammatory cytokine production was analyzed by RT-qPCR and ELISA. Activation of downstream signaling cascades known to be upregulated in TED and involved in tissue remodeling (PI3K/Akt and MAPK/Erk) were detected by Western blot.
Results :
IGF1R activation induced proliferation and PI3K/Akt signaling in OFs while smoke exposure increased inflammatory cytokine levels. Ligand activation of AHR reduced PI3K/Akt, MAPK/Erk signaling and cell proliferation. In contrast, knockout of AHR resulted in increased proliferation, increased inflammatory cytokine expression and elevated MAPK/Erk signaling.
Conclusions :
These studies show that AHR can block IGF1R mediated proliferation and PI3K/Akt signaling in OFs. AHR also reduces MAPK/Erk signaling driven by cigarette smoke exposure. These data suggest that the AHR pathway is a promising target to attenuate detrimental signaling and tissue remodeling that occurs in TED.
This is a 2021 ARVO Annual Meeting abstract.