Simvastatin Inhibits CYR61 Expression in Orbital Fibroblasts in Graves' Ophthalmopathy through the Regulation of FoxO3a Signaling.

Yi-Hsuan Wei,Chang-Hao Yang,Chia-Chun Wang,Shu-Lang Liao,Sen-Hsu Wang,Wan-Chun Tang,Saravanan Subramanian

doi:10.1155/2021/8888913

Abstract

Graves' ophthalmopathy (GO), which is characterized by orbital tissue inflammation, expansion, and fibrosis, is the ocular manifestation in 25% to 50% of patients with Graves' disease. As the pathology of GO is driven by autoimmune inflammation, many proinflammatory cytokines/chemokines, including TNF-α, IL-1β, IL-6, and CCL20, are crucial in the pathogenesis of GO to activate the orbital fibroblasts. Cysteine-rich protein 61 (CYR61), which is known to regulate cell proliferation, adhesion, and migration, plays a proinflammatory role in the pathogenesis of many inflammatory diseases, such as rheumatoid arthritis. CYR61 was considered a potential biomarker of GO in recent studies. Statins, which are cholesterol-lowering drugs, were found to reduce the risk of GO, probably through their anti-inflammatory and immunomodulatory effects. In this study, we established a link between CYR61 and statins in the pathogenesis and potential treatment for GO. Firstly, our data showed the overexpression of CYR61 in the orbital tissue (n = 4) and serum specimens (n = 6) obtained from the patients with inactive GO. CYR61 could induce the production of IL-6 and CCL20 in cultured GO orbital fibroblasts. The expression of CYR61 in cultured GO orbital fibroblasts was upregulated via TNF-α stimulation. Secondly, we pretreated cultured GO orbital fibroblasts using simvastatin, a statin, followed by TNF-α stimulation. The data revealed that simvastatin could inhibit TNF-α-induced CYR61 expression by modulating the activity of transcription factor FoxO3a. Our results provided insights into some cellular mechanisms that may explain the possible protective effects of simvastatin against the development of GO.

Highlights

Graves’ disease (GD) is a common autoimmune disease in which stimulatory autoantibodies bind to the thyroidstimulating hormone receptor (TSHR), resulting in increased thyroid gland activity and growth
We stimulated Graves’ ophthalmopathy (GO) orbital fibroblasts with TNF-α to induce the synthesis of Cysteine-rich protein 61 (CYR61), which may further induce other cytokines, as shown in many studies [26]
We demonstrated that CYR61 induced the expression of IL-6 and C chemokine ligand 20 (CCL20), which are both biomarkers for GO [16, 27]

Summary

Introduction

Graves’ disease (GD) is a common autoimmune disease in which stimulatory autoantibodies bind to the thyroidstimulating hormone receptor (TSHR), resulting in increased thyroid gland activity and growth. 25 to 50% of patients with GD develop ocular manifestations, known as Graves’ ophthalmopathy (GO), which is characterized by orbital inflammation, fibrosis, and tissue remodeling. TSHR and insulin-like growth factor receptor (IGF-1R) are the major autoantigens that are overexpressed in the orbital tissue of individuals with GO [2]. Orbital fibroblasts appear to play a crucial role in GO. They display a series of cell surface receptors and produce numerous proinflammatory cytokines and chemokines. These cause massive infiltration of T and B cells, hyaluronan accumulation, orbital adipogenesis, and tissue fibrosis [3]

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