MiR-193b-3p-ERBB4 axis regulates psoriasis pathogenesis via modulating cellular proliferation and inflammatory-mediator production of keratinocytes.
MiR-193b-3p-ERBB4 axis regulates psoriasis pathogenesis via modulating cellular proliferation and inflammatory-mediator production of keratinocytes.
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MiR-193b-3p-ERBB4 轴通过调节细胞增殖和角质形成细胞炎症介质的产生来调节银屑病发病机制
DOI：
10.1038/s41419-021-04230-5
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发表时间：
2021-10-19
影响因子：
9
通讯作者：
Yu B
中科院分区：
文献类型：
--
作者：
Huang C;Zhong W;Ren X;Huang X;Li Z;Chen C;Jiang B;Chen Z;Jian X;Yang L;Liu X;Huang H;Shen C;Chen X;Dou X;Yu B
银屑病是一种自身炎症性皮肤病，其特征在于表皮角质形成细胞的异常活化、异常的新血管形成和免疫细胞的失调。MicroRNA是一类非编码的小分子RNA，主要参与基因表达的转录后调控。近年来，越来越多的证据表明，microRNA在银屑病患者体内表达失调，在银屑病发病机制中发挥重要作用。miR-193 b-3 p的下调已被确定与银屑病的发展相关。然而，miR-193 b-3 p在银屑病发病机制中的确切功能和作用机制尚不清楚。在这项研究中，我们证实了miR-193 b-3 p在银屑病患者、银屑病样炎症细胞模型和咪喹莫特（IMQ）诱导的小鼠模型中的下调。miR-193 b-3 p水平与患者银屑病面积和严重程度指数（PASI）评分呈负相关。此外，miR-193 B-3 p抑制角质形成细胞的增殖、炎症因子分泌以及STAT 3和NF-κB信号通路。重要的是，皮内注射agomiR-193 b-3 p阻断了MQ诱导的小鼠模型中的银屑病样炎症，而apomiR-193 b-3 p增强了银屑病样炎症。生物信息学分析和双荧光素酶报告基因检测结果表明，miR-193 b-3 p靶向ERBB 4 3 ′端非翻译区（UTR）。此外，ERBB 4诱导角质形成细胞增殖、炎症因子产生以及STAT 3和NF-κB通路。最重要的是，ERBB 4的强制表达可以减弱miR-193 b-3 p在角质形成细胞中的作用，表明miR-193 b-3 p通过直接靶向ERBB 4抑制角质形成细胞活化。总之，我们的研究结果表明，miR-193 b-3 p-ERBB 4轴是银屑病角质形成细胞过度增殖和异常炎症因子分泌的基础，提供了一种新的microRNA相关的致病机制和银屑病的潜在治疗靶点。
Psoriasis is an auto-inflammatory skin disease characterized by abnormal activation of epidermal keratinocytes, aberrant neovascularization, and dysregulation of immune cells. MicroRNAs are small non-coding RNAs that mainly function in the post-transcriptional regulation of gene expression. Recently, accumulating evidence has demonstrated that expression of microRNAs is dysregulated in psoriasis patients and microRNAs play key roles in psoriasis pathogenesis. Downregulation of miR-193b-3p has been identified to be associated with psoriasis development. However, the precise functions and action mechanisms of miR-193b-3p in psoriasis pathogenesis remain unclear. In this study, we confirmed the downregulation of miR-193b-3p in psoriasis patients, psoriasis-like inflammatory cellular models, and an imiquimod (IMQ) -induced mouse model. A negative correlation was found between miR-193b-3p level and patient Psoriasis Area and Severity Index (PASI) score. Furthermore, miR-193b-3p suppressed proliferation, inflammatory-factor secretion, and the STAT3 and NF-κB signaling pathways in keratinocytes. Importantly, intradermal injection of agomiR-193b-3p blocked, whereas antagomiR-193b-3p augmented, the psoriasis-like inflammation in the IMQ-induced mouse model. Bioinformatics analysis and the dual-luciferase reporter assay showed that miR-193b-3p targets ERBB4 3ʹ untranslated region (UTR). In addition, ERBB4 induced proliferation, inflammatory-factor production, and the STAT3 and NF-κB pathways in keratinocytes. Most importantly, forced expression of ERBB4 could attenuate the effects of miR-193b-3p in keratinocytes, indicating that miR-193b-3p inhibits keratinocyte activation by directly targeting ERBB4. In conclusion, our findings demonstrated that the miR-193b-3p–ERBB4 axis underlies the hyperproliferation and aberrant inflammatory-factor secretion of psoriatic keratinocytes, providing a novel, microRNA-related causal mechanism and a potential therapeutic target in psoriasis.
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DOI：
10.4049/jimmunol.0803721
发表时间：
2009-09-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Goodman WA;Levine AD;Massari JV;Sugiyama H;McCormick TS;Cooper KD
通讯作者：
Cooper KD
影响因子：
10.3
作者：
Raaby, L.;Langkilde, A.;Iversen, L.
通讯作者：
Iversen, L.
DOI：
10.1016/j.jaci.2017.07.004
发表时间：
2017-09
期刊：
The Journal of allergy and clinical immunology
影响因子：
--
作者：
Hawkes JE;Chan TC;Krueger JG
通讯作者：
Krueger JG
影响因子：
4.8
作者：
Dai, Xin;Chen, Xi;Xia, Lu
通讯作者：
Xia, Lu
影响因子：
3.6
作者：
Lovendorf, Marianne B.;Mitsui, Hiroshi;Skov, Lone
通讯作者：
Skov, Lone