Department of Rheumatology, Huashan Hospital, Fudan University, Shanghai, China.
Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
Immunol Invest. 2023 Nov;52(6):703-716. doi: 10.1080/08820139.2023.2222746. Epub 2023 Jul 4.
Systemic sclerosis (SSc) is a rare rheumatic disease characterized by vascular damage, dysregulated immune response, and fibrosis. Interleukin-11 (IL-11) is upregulated in SSc. This study aimed to investigate the pathological and therapeutic role of the IL-11 trans-signaling pathway in SSc.
Plasma IL-11 level was evaluated in 32 patients with SSc and 15 healthy controls, while the expression levels of ADAM10, ADAM17, IL-11, IL-11 Rα, or IL-11 co-stained with CD3 or CD163 in the skin of SSc patients and healthy controls were analyzed. Fibroblasts were treated with IL-11 and ionomycin to evaluate the profibrotic effect of IL-11 trans-signaling pathway. TJ301 (sgp130Fc) and WP1066 (a JAK2/STAT3 inhibitor) intervention groups were set up to investigate the antifibrotic effect of targeting IL-11.
Levels of plasma IL-11 were extremely low in most SSc patients and healthy controls. In contrast, levels of IL-11, IL-11 Rα, and ADAM10, but not ADAM17, were significantly elevated in the skin of SSc patients. Moreover, the numbers of IL-11 CD3 cells and IL-11 CD163 cells were increased in the skin of SSc patients. Besides, IL-11 and ADAM10 were also elevated in the skin and pulmonary of bleomycin-induced SSc mouse. Fibroblasts co-stimulated with IL-11 and ionomycin showed increased expression of COL3 and phosphorylation of STAT3, which could be inhibited by TJ301 or WP1066. TJ301 also ameliorated skin and lung fibrosis in BLM-induced SSc mouse.
IL-11 induces fibrosis in SSc by regulating the trans-signaling pathway. Blockage of sgp130Fc or inhibition of the JAK2/STAT3 pathway could ameliorate the profibrotic effect of IL-11.
系统性硬化症（SSc）是一种罕见的风湿性疾病，其特征为血管损伤、免疫反应失调和纤维化。白细胞介素 11（IL-11）在 SSc 中上调。本研究旨在探讨 IL-11 转信号通路在 SSc 中的病理和治疗作用。
评估了 32 例 SSc 患者和 15 例健康对照者的血浆 IL-11 水平，分析了 SSc 患者和健康对照者皮肤中 ADAM10、ADAM17、IL-11、IL-11Rα 或 IL-11 与 CD3 或 CD163 共染色的表达水平。用 IL-11 和离子霉素处理成纤维细胞，以评估 IL-11 转信号通路的促纤维化作用。设立 TJ301（sgp130Fc）和 WP1066（JAK2/STAT3 抑制剂）干预组，以研究靶向 IL-11 的抗纤维化作用。
大多数 SSc 患者和健康对照者的血浆 IL-11 水平极低。相比之下，SSc 患者皮肤中 IL-11、IL-11Rα 和 ADAM10 的水平显著升高，但 ADAM17 水平没有升高。此外，SSc 患者皮肤中 IL-11 CD3 细胞和 IL-11 CD163 细胞的数量增加。此外，博来霉素诱导的 SSc 小鼠皮肤和肺组织中也升高了 IL-11 和 ADAM10。用 IL-11 和离子霉素共刺激成纤维细胞，可增加 COL3 的表达和 STAT3 的磷酸化，而 TJ301 或 WP1066 可抑制这些作用。TJ301 还可改善 BLM 诱导的 SSc 小鼠的皮肤和肺纤维化。
IL-11 通过调节转信号通路诱导 SSc 纤维化。阻断 sgp130Fc 或抑制 JAK2/STAT3 通路可改善 IL-11 的促纤维化作用。
