Disabled-2 参与系统性硬皮病的皮肤纤维化。
Involvement of Disabled-2 on skin fibrosis in systemic sclerosis.
机构信息
Ministry of Education Key Laboratory of Contemporary Anthropology, Department of Anthropology and Human Genetics, School of Life Sciences, Fudan University, Shanghai, China.
Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.
出版信息
J Dermatol Sci. 2020 Jul;99(1):44-52. doi: 10.1016/j.jdermsci.2020.05.009. Epub 2020 Jun 2.
BACKGROUND
Systemic sclerosis (SSc) is a connective tissue disease characterized by inflammation and fibrosis. Our previous research found Disabled-2 (DAB2) expression was significantly downregulated by salvianolic acid B, a small molecular medicine which attenuated experimental skin fibrosis of SSc. These suggest that DAB2 plays an important role in SSc skin fibrosis, but the role of DAB2 in SSc remains unclear.
OBJECTIVES
To investigate the role of DAB2 in SSc.
METHODS
DAB2 expression level was detected in the skin and peripheral blood mononuclear cells of SSc patients. Bleomycin (BLM)-induced SSc mice and primary SSc skin fibroblasts were used to investigate the effect of DAB2 downregulation on fibrosis. RNA-seq transcriptome analysis was performed to underlie the mechanism of DAB2 in fibroblasts.
RESULTS
DAB2 expression was enhanced in SSc lesion skin and was positively correlated with fibrotic genes, such as α-SMA and PAI-1. The in vivo study revealed that DAB2 downregulation alleviated skin fibrosis, alleviating skin thickness and reducing collagen deposition, and DAB2 knockdown ameliorated the inflammatory cell infiltration. The in vitro study showed that DAB2 knockdown reduced extracellular matrix genes and proteins expression. Moreover, Transcriptome analysis revealed TGF-β and focal adhesion signaling pathways were the main downregulated pathways involved in DAB2 siRNA treated fibroblasts.
CONCLUSIONS
Taken together, our results revealed that DAB2 was increased in SSc skin, and DAB2 downregulation inhibited BLM-induced mouse skin fibrosis and SSc skin fibroblasts activation. DAB2 played an important role in the pathogenesis of SSc and DAB2 modulation may represent a potential therapeutic method for SSc.
背景
系统性硬化症（SSc）是一种以炎症和纤维化为特征的结缔组织疾病。我们之前的研究发现，丹酰基二乙酰胺 2（DAB2）的表达被丹酚酸 B 显著下调，丹酚酸 B 是一种小分子药物，可减轻 SSc 的实验性皮肤纤维化。这些表明 DAB2 在 SSc 皮肤纤维化中发挥重要作用，但 DAB2 在 SSc 中的作用尚不清楚。
目的
研究 DAB2 在 SSc 中的作用。
方法
检测 SSc 患者皮肤和外周血单个核细胞中的 DAB2 表达水平。使用博来霉素（BLM）诱导的 SSc 小鼠和原代 SSc 皮肤成纤维细胞，研究 DAB2 下调对纤维化的影响。进行 RNA-seq 转录组分析以阐明 DAB2 在成纤维细胞中的作用机制。
结果
DAB2 的表达在 SSc 病变皮肤中增强，并与纤维化基因如α-SMA 和 PAI-1 呈正相关。体内研究表明，DAB2 下调可减轻皮肤纤维化，减轻皮肤厚度和减少胶原沉积，DAB2 敲低可改善炎症细胞浸润。体外研究表明，DAB2 敲低可降低细胞外基质基因和蛋白的表达。此外，转录组分析显示，TGF-β和黏着斑信号通路是 DAB2 siRNA 处理的成纤维细胞中主要下调的通路。
结论
综上所述，我们的研究结果表明，DAB2 在 SSc 皮肤中增加，DAB2 下调抑制 BLM 诱导的小鼠皮肤纤维化和 SSc 皮肤成纤维细胞激活。DAB2 在 SSc 的发病机制中起重要作用，DAB2 的调节可能代表 SSc 的一种潜在治疗方法。
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