Abstract
Purpose :
Graves' ophthalmopathy (GO) is a prevalent orbital disease that can lead to disfigurement and blindness. The inflammatory expansion of orbital adipose tissue is a core pathological feature of GO, of which the pathological mechanism is not yet clear. Protein arginine methyltransferase 6 (PRMT6) is a type I PRMT that is involved in the regulation of immune response and inflammation. Herein, we aimed to explore the role of PRMT6 in the inflammatory expansion of orbital adipose tissue in GO.
Methods :
Orbital adipose tissue samples of GO patients were collected from surgical wastes during orbital decompression. The expression of PRMT6 and its co-localization with adipose tissue macrophages (ATMs) were assessed. A GO mouse model was established by administering an adenovirus expressing human thyrotropin receptor A subunit. Body weight, serum autoantibodies (TRAb) and total thyroxine (TT4) levels were measured to evaluate thyroid function. Besides, histological examinations of orbital tissues and thyroid glands were conducted. Eye photos and MRI images were captured to assess the manifestation of GO. In addition, RAW264.7 and bone marrow-derived macrophages (BMDM) were employed in this study to investigate the impact of PRMT6 on macrophage polarization.
Results :
The expression of PRMT6 was found to be up-regulated in the orbital adipose tissue of GO and positively correlated with the clinical activity score and exophthalmos of GO patients. Besides, PRMT6 expression showed significant co-localization with ATMs, which was found to be M1-polarized in GO. A long-term GO mouse model was successfully established. Treatment with EPZ020411, a small-molecule inhibitor of PRMT6, effectively suppressed the inflammatory expansion of orbital adipose tissue, and improved the ocular symptoms in GO mice. In addition, inhibition of PRMT6 through PRMT6 siRNA or EPZ020411 suppressed the M1 polarization of RAW264.7 and BMDM.
Conclusions :
Our study has provided insights into the involvement of PRMT6 in the inflammatory expansion of orbital adipose tissue in GO, thereby indicating PRMT6 as a potential therapeutic target in GO.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.