Targeting miR-155 to Treat Experimental Scleroderma.
Targeting miR-155 to Treat Experimental Scleroderma.
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靶向 miR-155 治疗实验性硬皮病
DOI：
10.1038/srep20314
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发表时间：
2016-02-01
影响因子：
4.6
通讯作者：
Fu Q
中科院分区：
文献类型：
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作者：
Yan Q;Chen J;Li W;Bao C;Fu Q
硬皮病是一种难治的自身免疫性皮肤纤维化疾病。研究皮损皮肤中微小核糖核酸（microRNA，miRNA）的变化，可能为该病的治疗提供新途径。在此，我们发现，无论是系统性还是局限性硬皮病患者的皮损皮肤组织中，miR - 155的表达均上调，且与纤维化面积相关。随后，我们在临床前硬皮病模型中证实了miR - 155作为治疗靶点的潜力。miR - 155基因敲除（miR - 155−/− ）小鼠对博来霉素诱导的皮肤纤维化具有抗性。此外，局部应用抗miR - 155（antagomiR - 155）能够有效治疗皮下注射博来霉素致敏的小鼠。在原代皮肤成纤维细胞中，沉默miR - 155可同时抑制胶原蛋白合成功能，以及Wnt/β - 连环蛋白（Wnt/β - catenin）和蛋白激酶B（Akt）这两条促纤维化信号通路的信号强度。我们进一步表明，如先前报道，miR - 155可通过直接靶向酪蛋白激酶1α（CK1α）和含Src同源2结构域的肌醇磷酸酶 - 1（SHIP - 1）来调控这两条信号通路。博来霉素刺激后，miR - 155基因敲除小鼠或接受局部抗miR - 155治疗的小鼠，其皮肤中的Wnt/β - catenin和Akt信号受到抑制。综上所述，我们的数据表明，沉默miR - 155有望成为治疗皮肤纤维化的一种有效方法，尤其是局部应用。
Scleroderma is a refractory autoimmune skin fibrotic disorder. Alterations of microRNAs in lesional skin could be a new approach to treating the disease. Here, we found that expression of miR-155 was up regulated in lesional skin tissue from patients with either systemic or localized scleroderma and correlated with fibrosis area. Then we demonstrated the potential of miR-155 as a therapeutic target in pre-clinical scleroderma models. MiR-155−/−mice were resistant to bleomycin induced skin fibrosis. Moreover, topical antagomiR-155 could effectively treat mice primed with subcutaneous bleomycin. In primary skin fibroblast, miR-155 silencing could inhibit collagen synthesis function, as well as signaling intensity of two pro-fibrotic pathways, Wnt/β-catenin and Akt, simultaneously. We further showed that miR-155 could regulate the two pathways via directly targeting casein kinase 1α (CK1α) and Src homology 2-containing inositol phosphatase-1 (SHIP-1), as previous reports. Mice with miR-155 knockout or topical antagomir-155 treatment showed inhibited Wnt/β-catenin and Akt signaling in skin upon bleomycin challenge. Together, our data suggest the potential of miR-155 silencing as a promising treatment for dermal fibrosis, especially in topical applications.