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

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MeSH: Adult ; Autophagy* / physiology ; Cells, Cultured ; Endoplasmic Reticulum Stress* / genetics ; Endoribonucleases* / genetics ; Endoribonucleases* / metabolism ; Female ; Fibroblasts* / metabolism ; Fibrosis ; Graves Ophthalmopathy* / genetics ; Graves Ophthalmopathy* / metabolism ; Graves Ophthalmopathy* / pathology ; Humans ; Macrolides / pharmacology ; Macrolides / therapeutic use ; Male ; Middle Aged ; Protein Serine-Threonine Kinases* / genetics ; Protein Serine-Threonine Kinases* / metabolism ; RNA, Small Interfering / genetics ; Transforming Growth Factor beta / metabolism

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

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.