Identification of a novel PPARbeta/delta/miR-21-3p axis in UV-induced skin inflammation [human miRNA-seq]

Although excessive exposure to UV is widely recognized as a major factor leading to skin perturbations and cancer, the complex mechanisms underlying inflammatory skin disorders resulting from UV exposure remain incompletely characterized. The nuclear hormone receptor PPARbeta/delta is known to control cutaneous repair and UV-induced cancer development. Here, we describe a novel PPARbeta/delta-dependent molecular cascade involving TGFbeta-1 and miR-21-3p, which is activated in the epidermis in response to UV exposure. We establish that the passenger miRNA miR-21-3p, that we identify as a novel UV-induced miRNA in the epidermis, plays a pro-inflammatory function in keratinocytes, and that its high level of expression in human skin is associated with psoriasis and squamous cell carcinomas. Finally, we provide evidence that inhibition of miR-21-3p reduces UV-induced cutaneous inflammation in ex vivo human skin biopsies, thereby underlining the clinical relevance of miRNA-based topical therapies for cutaneous disorders. Epidermis and dermis, PPARB KO vs WT, 3-4 biological replicates per condition尽管过度紫外线（UV）暴露已被广泛认为是引发皮肤损伤与癌变的关键诱因，但紫外线暴露所致炎症性皮肤疾病的复杂发病机制仍未完全阐明。已知核激素受体PPARβ/δ（PPARbeta/delta）可调控皮肤修复以及紫外线诱导的癌变进程。本研究中，我们报道了一条全新的、依赖于PPARβ/δ的分子级联反应，该反应涉及转化生长因子β-1（TGFbeta-1）与miR-21-3p，可在表皮中被紫外线暴露激活。我们证实，我们在表皮中鉴定出的新型紫外线诱导型microRNA（miRNA）——乘客链miR-21-3p，可在角质形成细胞中发挥促炎功能；且该分子在人体皮肤中的高表达与银屑病（psoriasis）及鳞状细胞癌（squamous cell carcinomas）密切相关。最后，我们提供实验证据表明，抑制miR-21-3p可减轻离体人体皮肤活检组织中的紫外线诱导性皮肤炎症，这凸显了基于miRNA的皮肤疾病局部靶向疗法的临床应用价值。实验分组：表皮与真皮组织，PPARβ/δ基因敲除（PPARB KO）组与野生型（WT）组，每组设置3~4次生物学重复。