Department of Immunology and Pathophysiology, National Institute of Geriatrics Rheumatology and Rehabilitation, Warsaw, Poland.
Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy of the Polish Academy of Sciences, Wroclaw, Poland.
Eur J Clin Invest. 2017 Aug;47(8):555-564. doi: 10.1111/eci.12776. Epub 2017 Jul 18.
Systemic sclerosis (SSc) is a chronic autoimmune disease characterised by tissue fibrosis and immune abnormalities. Recent evidence suggests that activated circulating monocytes from patients with SSc play an important role in early stages of SSc pathogenesis due to enhanced expression of tissue inhibitor of metalloproteinases 1 (TIMP-1), IL-8 and reactive oxygen species (ROS) induction. However, the exact factors that contribute to chronic inflammation and subsequently fibrosis progression are still unknown.
The expression pattern of IL-8, TIMP-1, AP-1 transcription factor-Fra2 and ROS induction in peripheral blood monocytes following DZNep (histone methyltransferase inhibitor) and TLR8 agonist stimulation was investigated. Exogenous microRNA-5196, which is predicted to bind 3'UTR of Fra2 gene, was delivered to reverse profibrotic phenotype in monocytes. Expression of circulating microRNA-5196 was correlated with SSc parameters.
DZNep + TLR8 agonist stimulation enhanced profibrotic TIMP-1, IL-8 and ROS generation in HC and SSc monocytes. As opposed by the decrease of miRNA-5196 and antioxidant SOD1 expression in SSc monocytes. Exogenous delivery of microRNA-5196 reduced Fra2 and TIMP-1 expression suggesting that it may be used as a potential modulator of fibrogenesis in SSc. Circulating microRNA-5196 was significantly increased in SSc and positively correlated with CRP level but not with Rodnan skin score or ESR.
These results suggest that microRNA-5196 can be used as a potential biomarker characterising SSc. Overall, this study may open new possibilities for the development of microRNA-5196-based diagnostics and therapy in early phases of SSc.
系统性硬化症（SSc）是一种慢性自身免疫性疾病，其特征在于组织纤维化和免疫异常。最近的证据表明，由于组织抑制剂金属蛋白酶 1（TIMP-1）、白细胞介素 8（IL-8）和活性氧（ROS）诱导的表达增强，来自 SSc 患者的激活循环单核细胞在 SSc 发病机制的早期阶段发挥重要作用。然而，导致慢性炎症和随后纤维化进展的确切因素仍不清楚。
研究了 DZNep（组蛋白甲基转移酶抑制剂）和 TLR8 激动剂刺激后外周血单核细胞中 IL-8、TIMP-1、AP-1 转录因子-Fra2 和 ROS 诱导的表达模式。外源性 microRNA-5196，预测与 Fra2 基因 3'UTR 结合，被递送到单核细胞中以逆转成纤维表型。循环 microRNA-5196 的表达与 SSc 参数相关。
DZNep+TLR8 激动剂刺激增强了 HC 和 SSc 单核细胞的促纤维化 TIMP-1、IL-8 和 ROS 生成。相反，SSc 单核细胞中的 microRNA-5196 和抗氧化酶 SOD1 表达减少。外源性递送 microRNA-5196 降低了 Fra2 和 TIMP-1 的表达，表明它可能被用作 SSc 纤维化的潜在调节剂。循环 microRNA-5196 在 SSc 中显著增加，与 CRP 水平呈正相关，但与 Rodnan 皮肤评分或 ESR 无关。
这些结果表明 microRNA-5196 可作为 SSc 的潜在生物标志物。总体而言，这项研究可能为 SSc 早期阶段基于 microRNA-5196 的诊断和治疗开辟新的可能性。
