The role of miR-203 in keratinocyte biology and psoriasis

Abstract: Psoriasis is one of the most common chronic inflammatory skin diseases. It is a life long suffering disease affecting approximately 2 to 3% of the population in Scandinavia. Significant progress has been made to understand the cellular immunology and biology of psoriasis. However, the cause is still unclear and we still lack a cure for this common and enigmatic disease. MicroRNAs (miRNAs) are 18-22 nucleotides non-coding RNAs that regulate gene expression at the post-transcriptional level by targeting mRNAs for translational suppression or degradation. Extensive studies in the last few years showed that miRNAs play important roles in physiological processes and diseases. Before our investigation, no connection had been established between miRNAs and psoriasis. The general aim of this thesis was to investigate the involvement of miRNAs in the pathogenesis of psoriasis and skin/keratinocyte biology. In paper I, we showed for the first time that psoriasis-affected skin has a specific microRNA expression profile compared with healthy human skin or with another chronic inflammatory skin disease, atopic eczema. Among the psoriasis-associated microRNAs, we identified one skin and keratinocyte-specific microRNA, miR-203. The up-regulation of miR-203 in psoriatic plaques was concurrent with the down-regulation of one of its evolutionary conserved target, suppressor of cytokine signaling 3 (SOCS-3), which is involved in inflammatory responses and keratinocyte functions. This paper unveiled the involvement of microRNAs in inflammatory skin diseases. In paper II, we particularly examined the role of miR-203 in keratinocyte differentiation. Out of 365 miRNAs tested, miR-203 was the most upregulated miRNA during keratinocyte differentiation. Furthermore, we found that upregulation of miR-203 is required for keratinocyte differentiation and is dependent on the activation of the PKC/AP-1 pathway. In paper III, we explored the expression of miR-203 during human skin morphogenesis. MiR-203 is barely detectable at 14 weeks of estimated gestation age (EGA). Its expression became prominent from week 17 and was most pronounced in the suprabasal layers of the epidermis. The direct targets of miR-203, p63 and SOCS-3, were preferentially expressed in the basal layer. Our results suggest miR-203 is involved in the regulation of human foetal skin development and provide a basis for further studies to investigate the role of miR-203 in this process. In paper IV, we studied the role of miR-203 in NF-κB signaling in keratinocytes. We found that overexpression of miR-203 in human primary keratinocytes suppressed NF-κB activity by 1) suppressing downstream genes in NF-κB pathway; 2) preventing the nuclear translocation of p65 and repressing NF-κB-driven promoter luciferase activity. The results suggested that miR-203 plays a potential role in keeping skin homeostasis and controlling inflammation by modulating NF-κB signaling. In conclusion, our data in the thesis suggest that miR-203 plays a role as ‘safety guard’ in skin by regulating inflammation-, differentiation-, proliferation- and morphogenesis-associated processes.