Institute of Rheumatology, Prague, Czech Republic.
1st Faculty of Medicine, Charles University, Prague, Czech Republic.
Rheumatology (Oxford). 2024 Mar 1;63(3):817-825. doi: 10.1093/rheumatology/kead295.
Our previous studies have demonstrated that the Damage Associated Molecular Pattern (DAMP) protein, S100A4, is overexpressed in the involved skin and peripheral blood of patients with SSc. It is associated with skin and lung involvement, and disease activity. By contrast, lack of S100A4 prevented the development of experimental dermal fibrosis. Herein we aimed to evaluate the effect of murine anti-S100A4 mAb 6B12 in the treatment of preestablished experimental dermal fibrosis.
The effects of 6B12 were assessed at therapeutic dosages in a modified bleomycin-induced dermal fibrosis mouse model by evaluating fibrotic (dermal thickness, proliferation of myofibroblasts, hydroxyproline content, phosphorylated Smad3-positive cell count) and inflammatory (leukocytes infiltrating the lesional skin, systemic levels of selected cytokines and chemokines) outcomes, and transcriptional profiling (RNA sequencing).
Treatment with 7.5 mg/kg 6B12 attenuated and might even reduce pre-existing dermal fibrosis induced by bleomycin as evidenced by reduction in dermal thickness, myofibroblast count and collagen content. These antifibrotic effects were mediated by the downregulation of TGF-β/Smad signalling and partially by reducing the number of leukocytes infiltrating the lesional skin and decrease in the systemic levels of IL-1α, eotaxin, CCL2 and CCL5. Moreover, transcriptional profiling demonstrated that 7.5 mg/kg 6B12 also modulated several profibrotic and proinflammatory processes relevant to the pathogenesis of SSc.
Targeting S100A4 by the 6B12 mAb demonstrated potent antifibrotic and anti-inflammatory effects on bleomycin-induced dermal fibrosis and provided further evidence for the vital role of S100A4 in the pathophysiology of SSc.
我们之前的研究表明，损伤相关分子模式（DAMP）蛋白 S100A4 在系统性硬化症（SSc）患者受累皮肤和外周血中过度表达。它与皮肤和肺部受累以及疾病活动有关。相比之下，缺乏 S100A4 可防止实验性皮肤纤维化的发展。在此，我们旨在评估鼠抗 S100A4 mAb 6B12 在治疗预先建立的实验性皮肤纤维化中的作用。
通过评估纤维化（皮肤厚度、肌成纤维细胞增殖、羟脯氨酸含量、磷酸化 Smad3 阳性细胞计数）和炎症（病变皮肤浸润的白细胞、选定细胞因子和趋化因子的系统水平以及转录谱），在改良博来霉素诱导的皮肤纤维化小鼠模型中评估 6B12 的作用。
用 7.5mg/kg 6B12 治疗可减轻甚至可能减少博来霉素诱导的预先存在的皮肤纤维化，表现为皮肤厚度、肌成纤维细胞计数和胶原含量减少。这些抗纤维化作用是通过下调 TGF-β/Smad 信号转导介导的，部分是通过减少病变皮肤浸润的白细胞数量和降低系统中 IL-1α、嗜酸性粒细胞趋化因子、CCL2 和 CCL5 的水平来实现的。此外，转录谱分析表明，7.5mg/kg 6B12 还调节了与 SSc 发病机制相关的几个促纤维化和促炎过程。
6B12 mAb 靶向 S100A4 对博来霉素诱导的皮肤纤维化具有强大的抗纤维化和抗炎作用，并进一步证明 S100A4 在 SSc 病理生理学中的重要作用。
