Comparative miRNA expression of normal skin from control and lesional skin from mice. Mus musculus

The efficacy of monoclonal antibodies against either interleukin (IL)-17 or the IL-17 receptor in psoriasis therapy provides strong evidence that IL-17 is the major inflammatory mediation in this disease. However, how IL-17 induces epidermal hyperplasia in psoriasis remains largely unknown. Here, we show that IL-17 actives NF-kB in keratinocytes and initiates the NF-kB-dependent transcription of microRNA-31 (miR-31), one of the most abundant microRNAs in the epidermis of lesional skin of psoriasis and two related mouse models. Similar to IL-17 deficiency (IL-17-/-), knocking out miR-31 (miR-31-/-) or targeting it by antagomir-31 prevents keratinocytes Ki67 expression and inhibits acanthosis and dermal inflammation in psoriasis mouse model. Moreover, PPP6c, a negative regulator restricting G0/G1 to G2/M phase progression in the cell cycle, is diminished in human psoriatic epidermis and is directly targeted by miR-31. Inhibition of ppp6c is functionally important for the biological effects of miR-31 in the development of epidermal hyperplasia. Thus, our data define IL-17-inducede miR-31 and its target ppp6c as critical factors for hyperproliferative epidermis in psoriasis. Overall design: Epidermis samples from affected ears derived from 3 CD18hypo PL/J mice (DIS) or normal ears derived from 3 CD18hypo C57BL/6J mice(2128) were used for RNA extraction and hybridization on Affymetrix microarrays. We sought to compare miRNA expression of normal skin from control and lesional skin.

针对白细胞介素（interleukin, IL）-17或IL-17受体的单克隆抗体用于银屑病治疗的疗效，为IL-17是该疾病的核心炎症介导因子提供了坚实证据。然而，IL-17如何诱导银屑病表皮增生的具体机制，目前仍尚未完全明确。本研究发现，IL-17可激活角质形成细胞（keratinocyte）中的核因子κB（NF-κB），并启动依赖于NF-κB的微小RNA（microRNA，miRNA）-31（miR-31）转录——miR-31是银屑病皮损皮肤及两种相关小鼠模型表皮中丰度最高的微小RNA之一。与IL-17基因敲除（IL-17-/-）小鼠表型一致，敲除miR-31（miR-31-/-）或通过miR-31反义寡核苷酸拮抗剂（antagomir-31）靶向抑制miR-31，均可抑制角质形成细胞表达Ki67抗原（Ki67），并改善银屑病小鼠模型中的棘层肥厚与真皮炎症反应。此外，作为限制细胞周期由G0/G1期向G2/M期进展的负调控因子，PPP6c在人类银屑病表皮中表达显著下调，且可被miR-31直接靶向调控。PPP6c的功能抑制对于miR-31介导的表皮增生生物学效应至关重要。综上，本研究数据表明，IL-17诱导的miR-31及其靶基因PPP6c，是银屑病表皮过度增殖的关键调控因子。
总体实验设计：本研究从3只CD18hypo PL/J银屑病模型小鼠的病变耳部（DIS组）以及3只CD18hypo C57BL/6J正常小鼠的正常耳部（2128组）分离表皮样本，进行RNA提取后在Affymetrix基因芯片上完成杂交。本研究旨在对比对照组正常皮肤与银屑病皮损皮肤的微小RNA表达谱。