State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China.
Front Endocrinol (Lausanne). 2022 Feb 22;13:846106. doi: 10.3389/fendo.2022.846106. eCollection 2022.
Orbital fibrosis is a hallmark of tissue remodeling in thyroid-associated ophthalmopathy (TAO). Previous studies have shown that interleukin (IL)-11 plays a pivotal profibrotic role in various inflammatory and autoimmune diseases. However, the expression pattern of IL-11 in patients with TAO and whether IL-11 is mechanistically linked with pathological fibrosis remains unknown. In this study, we investigated IL-11 levels in the serum and orbital connective tissue of patients with TAO, and evaluated the correlation of these levels with the patient's clinical activity score. We also evaluated the expression pattern of IL-11Rα in orbital connective tissue. Furthermore, we elucidated the regulatory factors, profibrotic function, and downstream signaling pathways for IL-11 in TAO using studies. IL-11 levels in serum and orbital connective tissues were increased in patients with TAO, as compared with healthy controls. In addition, both levels were positively correlated with disease activity. Single-cell RNA sequencing of orbital connective tissue indicated that IL-11Rα was dominantly expressed in orbital fibroblasts (OFs). RNA sequencing of paired unstimulated and transforming growth factor (TGF)-β1-stimulated samples demonstrated that upregulation of IL-11 expression defined the dominant transcriptional response. IL-11 signaling was also confirmed to be downstream of TGF-β1 and IL-1β. Therefore, we deduced that IL-11 protein is secreted in an autocrine loop in TAO. We also indicated that IL-11 mediated the profibrotic phenotype switch by inducing the expression of myofibroblast differentiation markers, including α-smooth muscle actin and collagen type I α1, which could be abrogated by an anti-IL-11 neutralizing antibody. Furthermore, we revealed that extracellular regulated protein kinase may be a crucial factor in the pro-fibrotic, translationally specific signaling activity of IL-11. These data demonstrate that IL-11 plays a crucial role in orbital fibroblast phenotype switching and may be a potential therapeutic target candidate for the treatment of TAO.
眼眶纤维化是甲状腺相关眼病 (TAO) 组织重塑的标志。先前的研究表明，白细胞介素 (IL)-11 在各种炎症和自身免疫性疾病中发挥关键的促纤维化作用。然而，IL-11 在 TAO 患者中的表达模式以及 IL-11 是否与病理性纤维化有机制联系尚不清楚。在这项研究中，我们研究了 TAO 患者血清和眼眶结缔组织中的 IL-11 水平，并评估了这些水平与患者临床活动评分的相关性。我们还评估了 IL-11Rα 在眼眶结缔组织中的表达模式。此外，我们通过研究阐明了 TAO 中 IL-11 的调节因子、促纤维化功能和下游信号通路。与健康对照组相比，TAO 患者的血清和眼眶结缔组织中的 IL-11 水平升高。此外，这两个水平都与疾病活动呈正相关。眼眶结缔组织的单细胞 RNA 测序表明，IL-11Rα 在眼眶成纤维细胞 (OFs) 中表达占主导地位。配对的未刺激和转化生长因子 (TGF)-β1 刺激样本的 RNA 测序表明，IL-11 表达的上调定义了主要的转录反应。IL-11 信号也被证实是 TGF-β1 和 IL-1β 的下游。因此，我们推断 TAO 中 IL-11 蛋白是在自分泌环中分泌的。我们还表明，IL-11 通过诱导肌成纤维细胞分化标志物（包括α-平滑肌肌动蛋白和胶原 Iα1）的表达来介导成纤维细胞表型转换，这可以被抗 IL-11 中和抗体阻断。此外，我们揭示细胞外调节蛋白激酶可能是 IL-11 促纤维化、翻译特异性信号活性的关键因素。这些数据表明，IL-11 在眼眶成纤维细胞表型转换中发挥关键作用，可能是治疗 TAO 的潜在治疗靶点候选物。
