IL-17 mediated downregulation of miR-101 facilitates expression of EZH2 to promote epidermal hyperplasia in psoriasis

Epidermal hyperplasia, a characteristic feature of psoriatic skin lesions, is epigenetically driven by Enhancer of Zeste homolog 2 (EZH2). EZH2 and EZH2-mediated trimethylation of histone H3 lysine 27 (H3K27me3) are both abnormally upregulated in psoriatic lesions. To identify microRNAs that could potentially target these epigenetic regulators we profiled miRNAs from psoriatic lesional skin in comparison with healthy skin. Analysis of the differentially expressed miRNAs revealed miR-101, as one of the most significant miRNA, consistently downregulated in psoriatic lesions compared to the healthy skin. A clear inverse correlation in the expression of miR-101 versus EZH2 was apparent in normal skin versus psoriatic lesional skin indicating that EZH2 is a potential target of miR-101, which was further confirmed by luciferase assay. Investigating the upstream effectors of the miR-101- EZH2 pathway in psoriasis, we identified the pro-inflammatory cytokine IL-17 as regulator of miR-101 expression. Here we propose a model, depicting a pathway triggered by IL-17 – mediated modulation of miR-101 expression, which in turn elicit sustained expression of EZH2, leading to enhanced keratinocyte proliferation and epidermal hyperplasia in psoriasis. Taken together, this indicates that miR-101 is a potential therapeutic target to alleviate the downstream effects of IL-17 mediated epidermal hyperplasia in psoriasis. Total RNA was extracted from healthy and psoriatic lesional skin by trizol lysis followed by extraction with Exiqon miRcury RNA extraction kit and subjected to exiqon microRNA microarray