Targeting miR-21 to Treat Psoriasis
Targeting miR-21 to Treat Psoriasis
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DOI：
10.1126/scitranslmed.3008089
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发表时间：
2014-02-26
影响因子：
17.1
通讯作者：
Wagner, Erwin F.
中科院分区：
文献类型：
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作者：
Guinea-Viniegra, Juan;Jimenez, Maria;Wagner, Erwin F.
牛皮癣是一种常见的炎症性皮肤病，治疗选择有限，其特点是角质形成细胞、免疫细胞和炎症介质之间复杂的相互作用。 MicroRNA (miRNA) 是基因表达的调节因子，在许多人类疾病中发挥着关键作用。许多 miRNA 被描述在银屑病中表达上调，但它们对疾病发展的因果作用尚未得到证实。我们证实，牛皮癣患者表皮病变中 miR-21 表达增加，这导致表皮 TIMP-3（基质金属蛋白酶 3 组织抑制剂）表达减少，并激活 TACE（肿瘤坏死因子-α 转换酶）/ADAM17（解整合素和金属蛋白酶 17）。使用患者来源的皮肤样本和银屑病小鼠模型，我们证明 miR-21 增加可能是 Jun/激活蛋白 1 (AP-1) 转录活性受损的结果，导致白介素 6 (IL-6)/信号转导器和转录激活剂 3 (Stat3) 通路的激活。通过锁核酸 (LNA) 修饰的抗 miR-21 化合物抑制 miR-21 可改善小鼠银屑病皮肤异种移植物和银屑病样小鼠模型中的疾病病理学。靶向 miR-21 可能代表治疗银屑病的潜在治疗选择。
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-alpha-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.