969 Epidermis-specific deletion of miR-149 exacerbates psoriasis-like skin inflammation

MicroRNAs (miRNAs) are important regulators of gene expression and have been implicated in immunity and inflammation. Chronic skin inflammation in psoriasis is maintained by inflammatory circuits involving infiltrating immune cells and keratinocytes. Recently we identified microRNA(miR)-149 to be suppressed in psoriasis keratinocytes and showed that it acts as a link between IFN-g and the TWEAK pathways. To further explore the role of miR-149 in keratinocyte immune responses and skin homeostasis, we have generated knockout mice with epidermis-specific deletion of miR-149 (miR-149 EKO). We report that miR-149 EKO mice are viable and display a normal skin phenotype in the absence of inflammatory stimuli. However, keratinocytes isolated from miR-149 EKO mice responded stronger to stimulation by TWEAK. Induction of psoriasiform skin inflammation by topical application of imiquimod (IMQ) led to exacerbated skin inflammation in miR-149 EKO mice compared to control mice, with increased epidermal thickness, increased infiltration of immune cells in the skin, as well as higher expression of psoriasis-associated inflammatory mediators. RNA sequencing analysis of IMQ-treated wild-type and miR-149 EKO skin revealed an enrichment of immune/inflammatory responses among differentially expressed genes in the skin of miR-149 EKO animals. Similarly, intradermal injection of IL-23 led to the exacerbation of skin inflammation in miR-149 EKO vs. wild-type mice, with increased ear thickness, epidermal thickness, and immune cell infiltration. Altogether, our results suggest that the downregulation of miR-149 amplifies skin inflammation in psoriasis by enhancing keratinocyte immune responses.