360 miR-378a is overexpressed in psoriasis keratinocytes and potentiates IL-17A-mediated inflammatory responses

Abstract

Psoriasis is an immune-mediated inflammatory skin disease with a strong genetic background, in which an interplay between infiltrating immune cells and keratinocytes contributes to chronic skin inflammation. The cytokine IL-17, produced by Th17 cells and other cell types, is central in the pathogenesis, and its main target cells are keratinocytes in which it induces cytokines, chemokines and antimicrobial peptides, which further amplify inflammation. Recently, we performed next-generation sequencing for small RNAs in keratinocytes separated by magnetic sorting of CD45neg cells from the epidermis from lesional and non-lesional skin from psoriasis patients. One of the miRNAs differentially expressed in psoriasis keratinocytes was miR-378a. Here, we investigated the function of miR-378a in keratinocytes in psoriasis. miR-378a was significantly up-regulated in keratinocytes of psoriasis skin lesions, as evidenced by RNAseq as well as qPCR on sorted keratinocytes obtained from a larger patient cohort. To investigate the regulation of miR-378a, cultured primary human keratinocytes were treated with a panel of cytokines. qPCR expression analysis of miR-378a showed that IL-17A significantly induced miR-378a, while other cytokines studied did not affect its expression. The NF-kB pathway inhibitor BAY 11-7082 prevented the induction of miR-378a by IL17A, indicating that miR-378a is regulated through the NF-kB pathway. Overexpression of miR-378a in primary keratinocytes potentiated IL-17A-mediated induction of inflammatory mediators in keratinocytes, such as the cytokines CCL20 and IL-8, and the antimicrobial peptide hBD2. Our findings suggest that upregulation of miR-378a in keratinocytes of psoriasis lesions enhances their inflammatory response to IL-17A, thereby amplifying IL-17A-mediated inflammation. Inhibition of miR-378a may have therapeutic potential in psoriasis.