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

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. 16 samples: 4 KO (Ppard-/-)and 4 WT (Ppard+/+) irradiated for 12 weeks; 4 KO and 4 WT without irradiation尽管过度紫外线（UV）暴露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致病机制仍未得到完全阐明。过氧化物酶体增殖物激活受体β/δ（PPARbeta/delta）已被证实可调控皮肤修复以及紫外线诱导的癌变进程。本研究报道了一条全新的、依赖于PPARbeta/delta的分子级联通路，该通路涉及转化生长因子β1（TGFbeta-1）与微小RNA-21-3p（miR-21-3p），并可在表皮中被紫外线暴露激活。本研究证实，作为表皮中新型紫外线诱导型微小RNA的过客链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及鳞状细胞癌密切相关。最后，本研究提供证据表明，抑制miR-21-3p可减轻离体人皮肤活检组织中紫外线诱导的皮肤炎症，从而凸显了基于微小RNA的外用疗法在皮肤疾病治疗中的临床应用价值。本实验共包含16份样本：4份基因敲除型（Ppard-/-，KO）样本与4份野生型（Ppard+/+，WT）样本经12周紫外线照射；另有4份基因敲除型与4份野生型样本未接受紫外线照射。