Yonsei Med J.  2024 Jul;65(7):397-405. 10.3349/ymj.2023.0294.

Role of Inositol-Requiring Enzyme 1 and Autophagy in the Pro-Fibrotic Mechanism Underlying Graves’ Orbitopathy

• Lee CE
• Kim JY
• Yoon JS
• Ko J

• KMID: 2557215
• DOI: http://doi.org/10.3349/ymj.2023.0294

Abstract

Purpose
Orbital fibroblasts play key roles in the pathogenesis of Graves’ orbitopathy (GO), and previous findings have shown that endoplasmic reticulum (ER) stress and autophagy also contribute to GO. In this study, we investigated the presently unclear roles of inositol-requiring enzyme 1 (IRE1) and related autophagy processes in the pro-fibrotic mechanism of GO.
Materials and Methods
Orbital adipose/connective tissues were obtained from eight GO patients and six normal individuals during surgery. GO fibroblasts were transfected with IRE1 small-interfering RNA and treated with bafilomycin A1 (Baf-A1) to evaluate the inhibitory effects of ER stress and autophagy, and protein-expression levels were analyzed through western blotting after stimulation with transforming growth factor (TGF)-β.
Results
TGF-β stimulation upregulated IRE1 in GO orbital fibroblasts, whereas silencing IRE1 suppressed fibrosis and autophagy responses. Similarly, Baf-A1, an inhibitor of late-phase autophagy, decreased the expression of pro-fibrotic proteins.
Conclusion
IRE1 mediates autophagy and the pro-fibrotic mechanism of GO, which provides a more comprehensive interpretation of GO pathogenesis and suggests potential therapeutic targets.

Keyword

Autophagy; endoplasmic reticulum stress; fibrosis; Graves’ orbitopathy; inositol-requiring enzyme 1; thyroid eye disease