Cigarette Smoking Drives Thyroid Eye Disease Progression via RAGE Signaling Activation

作者：Jin Liu, Jin Liu, Tianyi Zhu, Tianyi Zhu, Lianfei Fang, Li Yang, Weijin Qian, Lianfei Fang, Weiqi Zhang, Haiyang Zhang, Yi Wang, Baiguang Yu, Jing Sun, Bin Li, Dan Li, Dan Li, Yinwei Li, Yinwei Li, Sijie Fang, Sijie Fang, Huifang Zhou, Huifang Zhou · 发表于：Thyroid · 年份：2025 · DOI：10.1089/thy.2025.0062 · 被引用次数：9 · 研究领域：Ophthalmology and Eye Disorders、Glaucoma and retinal disorders、S100 Proteins and Annexins

Background:Thyroid eye disease (TED) is a sight-threatening autoimmune disease with cigarette smoking as one of the key risk factors. Cigarette smoking affects both the severity of TED and the patient’s response to medication. However, the underlying pathogenic mechanisms of smoking in TED remain unclear. Methods:Orbital fibroblasts (OFs) were extracted from patients with TED and non-TED controls, and treated with cigarette smoking extract (CSE). Luminex assays and Western blots were employed to examine inflammatory status and pathological phenotypes of OFs. A specific reactive oxygen species (ROS) probe was used to evaluate oxidative stress levels. RNA-sequencing of CSE-treated OFs was used to analyze differentially expressed genes. Immunofluorescence and RNA-sequencing were used to examine the expression of receptor for advanced glycation end products (RAGE) signaling molecules in patients. Small interfering RNA sequences and a RAGE-specific inhibitor were employed to investigate the effects of RAGE blockade on cigarette smoking-related pathological phenotypes. To validate our findings in vivo, we generated an adenovirus-induced TED mouse model with exposure to cigarette smoke. Results:Exposure to CSE resulted in an inflammatory phenotype of OFs together with higher levels of oxidative stress. OFs exposed to CSE presented susceptibility to transforming growth factor-β-induced myofibroblast differentiation, and 15-D-PGJ2-induced adipocyte differentiation, indicating pro-fibr...