F-BBVA-CNIO Cancer Cell Biology Program, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
Sci Transl Med. 2014 Feb 26;6(225):225re1. doi: 10.1126/scitranslmed.3008089.
Psoriasis is a common inflammatory skin disease with limited treatment options that is characterized by a complex interplay between keratinocytes, immune cells, and inflammatory mediators. MicroRNAs (miRNAs) are regulators of gene expression and play critical roles in many human diseases. A number of miRNAs have been described to be up-regulated in psoriasis, but their causal contribution to disease development has not been demonstrated. We confirm that miR-21 expression is increased in epidermal lesions of patients with psoriasis and that this leads to reduced epidermal TIMP-3 (tissue inhibitor of matrix metalloproteinase 3) expression and activation of TACE (tumor necrosis factor-α-converting enzyme)/ADAM17 (a disintegrin and metalloproteinase 17). Using patient-derived skin samples and mouse models of psoriasis, we demonstrate that increased miR-21 may be a consequence of impaired transcriptional activity of Jun/activating protein 1 (AP-1), leading to activation of the interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (Stat3) pathway. Inhibition of miR-21 by locked nucleic acid (LNA)-modified anti-miR-21 compounds ameliorated disease pathology in patient-derived psoriatic skin xenotransplants in mice and in a psoriasis-like mouse model. Targeting miR-21 may represent a potential therapeutic option for the treatment of psoriasis.
银屑病是一种常见的炎症性皮肤病，治疗选择有限，其特征是角质形成细胞、免疫细胞和炎症介质之间的复杂相互作用。微小 RNA（miRNA）是基因表达的调节剂，在许多人类疾病中发挥着关键作用。已经描述了许多 miRNA 在银屑病中上调，但它们对疾病发展的因果贡献尚未得到证明。我们证实 miR-21 的表达在银屑病患者的表皮损伤中增加，这导致表皮 TIMP-3（基质金属蛋白酶组织抑制剂 3）表达减少和 TACE（肿瘤坏死因子-α转化酶）/ADAM17（解整合素和金属蛋白酶 17）的激活。使用患者来源的皮肤样本和银屑病小鼠模型，我们证明增加的 miR-21 可能是 Jun/激活蛋白 1（AP-1）转录活性受损的结果，导致白细胞介素-6（IL-6）/信号转导和转录激活因子 3（Stat3）途径的激活。用锁核酸（LNA）修饰的抗 miR-21 化合物抑制 miR-21 可改善小鼠患者来源的银屑病皮肤异种移植和银屑病样小鼠模型中的疾病病理。靶向 miR-21 可能是治疗银屑病的一种潜在治疗选择。
