• Chae Eun Lee, Ji-Young Kim, Jin Sook Yoon, and JaeSang Ko.
• Department of Ophthalmology, Institute of Vision Research, Yonsei University College of Medicine, Seoul, Korea.
• Yonsei Med. J. 2024 Jul 1; 65 (7): 397405397-405.

PurposeOrbital 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 MethodsOrbital 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.ResultsTGF-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.ConclusionIRE1 mediates autophagy and the pro-fibrotic mechanism of GO, which provides a more comprehensive interpretation of GO pathogenesis and suggests potential therapeutic targets.© Copyright: Yonsei University College of Medicine 2024.

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