Argentino Giuseppe, Olivieri Bianca, Morandi Matteo, Bonisoli Giulio, Beri Ruggero, Tinazzi Elisa, Friso Simonetta
Internal Medicine Unit B, Department of Medicine, University of Verona, 37134 Verona, Italy.
Allergy Unit and Asthma Center, Verona Integrated University Hospital, 37134 Verona, Italy.
Int J Mol Sci. 2025 Mar 17;26(6):2699. doi: 10.3390/ijms26062699.
Systemic sclerosis (SSc) is a chronic autoimmune disorder characterized by fibrosis, immune dysregulation, and vascular abnormalities. Extracellular vesicles (EVs), secreted by immune cells, have been implicated in modulating fibroblast activity and are actively involved in SSc pathogenesis. This study aims to determine whether lymphomonocytic-derived EVs influence fibroblast proliferation and collagen synthesis in SSc. Fibroblasts from healthy donors (HDFs) and SSc patients (SScHDFs) were exposed to EVs derived from Jurkat and U937 cell lines stimulated under pro-inflammatory conditions using tumor necrosis factor-α (TNFα) or phorbol 12-myristate 13-acetate + ionomycin (PMA + IONO). Proliferation was assessed using CCK-8 assays, while collagen production was quantified via ELISA. Our findings demonstrate that EVs derived from PMA + IONO-stimulated Jurkat and U937 cells significantly reduced fibroblast proliferation in a dose-dependent manner. Notably, SScHDFs exhibited lower baseline proliferation and a diminished overall response to EV treatment. Collagen production was markedly reduced in both fibroblast types following exposure to PMA + IONO-stimulated EVs, whereas TNFα-stimulated EVs affected only HDFs. These findings suggest that EVs from activated immune cells modulate fibroblast function in SSc, potentially contributing to disease pathogenesis. Further research is warranted to elucidate the molecular mechanisms underlying these effects and to explore the therapeutic potential of targeting EV-mediated signaling in SSc.
系统性硬化症（SSc）是一种慢性自身免疫性疾病，其特征为纤维化、免疫失调和血管异常。免疫细胞分泌的细胞外囊泡（EVs）与调节成纤维细胞活性有关，并积极参与SSc的发病机制。本研究旨在确定淋巴细胞来源的EVs是否影响SSc中成纤维细胞的增殖和胶原蛋白合成。将来自健康供体的成纤维细胞（HDFs）和SSc患者的成纤维细胞（SScHDFs）暴露于来自Jurkat和U937细胞系的EVs，这些细胞系在促炎条件下使用肿瘤坏死因子-α（TNFα）或佛波醇12-肉豆蔻酸酯13-乙酸酯+离子霉素（PMA + IONO）进行刺激。使用CCK-8测定法评估增殖，而通过ELISA定量胶原蛋白的产生。我们的研究结果表明，来自PMA + IONO刺激的Jurkat和U937细胞的EVs以剂量依赖性方式显著降低成纤维细胞增殖。值得注意的是，SScHDFs表现出较低的基线增殖和对EV治疗的总体反应减弱。暴露于PMA + IONO刺激的EVs后，两种成纤维细胞类型的胶原蛋白产生均显著减少，而TNFα刺激的EVs仅影响HDFs。这些发现表明，活化免疫细胞来源的EVs调节SSc中成纤维细胞的功能，可能有助于疾病发病机制。有必要进行进一步研究以阐明这些作用的分子机制，并探索靶向SSc中EV介导信号传导的治疗潜力。
