miR-378a regulates keratinocyte responsiveness to interleukin-17A in psoriasis

Background Psoriasis is an immune-mediated inflammatory skin disease, in which an interplay between infiltrating immune cells and keratinocytes sustains chronic skin inflammation. Interleukin (IL)-17A is a key inflammatory cytokine in psoriasis and its main cellular targets are keratinocytes. Objectives To explore the role of miR-378a in psoriasis. Methods Keratinocytes obtained from psoriatic skin and healthy epidermis were separated by magnetic sorting, and the expression of miR-378a was analysed by quantitative polymerase chain reaction. The regulation and function of miR-378a was studied using primary human keratinocytes. The expression of miR-378a was modulated by synthetic mimics, and nuclear factor kappa B (NF-kappa B) activity and transcriptomic changes were studied. Synthetic miR-378a was delivered to mouse skin in conjunction with induction of psoriasiform skin inflammation by imiquimod. Results We show that miR-378a is induced by IL-17A in keratinocytes through NF-kappa B, C/EBP-beta and I kappa B zeta and that it is overexpressed in psoriatic epidermis. In cultured keratinocytes, ectopic expression of miR-378a resulted in the nuclear translocation of p65 and enhanced NF-kappa B-driven promoter activity even in the absence of inflammatory stimuli. Moreover, miR-378a potentiated the effect of IL-17A on NF-kappa B nuclear translocation and downstream activation of the NF-kappa B pathway. Finally, injection of miR-378a into mouse skin augmented psoriasis-like skin inflammation with increased epidermal proliferation and induction of inflammatory mediators. Mechanistically, miR-378a acts as a suppressor of NFKBIA/I kappa B zeta, an important negative regulator of the NF-kappa B pathway in keratinocytes. Conclusions Collectively, our findings identify miR-378a as an amplifier of IL-17A-induced NF-kappa B signalling in keratinocytes and suggest that increased miR-378a levels contribute to the amplification of IL-17A-driven skin inflammation in psoriasis. What is already known about this topic? Interleukin (IL)-17A induces production of inflammatory mediators in keratinocytes and is directly or indirectly responsible for many of the features observed in psoriatic skin. MicroRNAs (miRNAs) are regulators of gene expression and can regulate the duration or extent of inflammatory responses. The level of several miRNAs is altered in psoriatic skin lesions. What does this study add? We show that IL-17A induces miR-378a in keratinocytes and that miR-378a is overexpressed in psoriatic epidermis. Our findings demonstrate that miR-378a amplifies basal and IL-17A-induced nuclear factor kappa B signalling and cytokine production in keratinocytes. Injection of synthetic miR-378a into mouse skin exacerbates psoriasis-like skin inflammation. What is the translational message? Fine tuning the IL-17A-responsiveness of keratinocytes by modulating miR-378a and/or its targets may represent a new approach to break the vicious circle of inflammation in psoriasis. Our findings prompt further research to explore the potential of miRNA modulation in psoriasis and other inflammatory skin diseases.

Automated summary

The study reveals that miR-378a plays an amplifying role in IL-17A-induced NF-kappa B signaling in psoriasis, enhancing skin inflammation through nuclear translocation and production of inflammatory mediators.