miR-378a: an amplifier of the interleukin-17A response in keratinocytes.

MicroRNAs (miRNAs or miRs) are a group of single‐stranded short noncoding RNAs of approximately 22 nucleotides in length. They regulate the expression of protein‐coding genes at a post‐transcriptional level. Through the RNA‐induced silencing complex, miRNAs bind to the 3′‐untranslated region of their target mRNAs, leading to translational inhibition or degradation of these targets. miRNAs are known to play an important role in numerous biological and physiological processes, and abnormal miRNA expression has been discovered in many human diseases, including psoriasis. ,

Psoriasis is a common chronic immune‐mediated skin disease affecting approximately 125 million people worldwide. The pathogenesis of psoriasis is not fully understood but it is believed to be driven by an abnormal interplay between T cells and keratinocytes. In particular, the proinflammatory cytokine interleukin (IL)‐17A is known to play a crucial role in psoriasis pathogenesis. This is shown by drugs targeting IL‐17A, which have proven to be highly effective in psoriasis treatment. Although the keratinocytes are believed to be the key cellular target of IL‐17A‐induced psoriasis, the mechanism is not completely elucidated.

In this issue of the BJD, Xia and colleagues systematically investigated the interplay between miR‐378a and IL‐17A in human keratinocytes. Sequencing of small RNAs showed miR‐378a to be overexpressed in keratinocytes isolated from lesional psoriatic skin compared with nonlesional psoriatic skin and healthy skin, a finding that was also previously published by the same group. In a psoriasis mouse model, intradermal injection of miR‐378a was found to exacerbate psoriasis‐like skin inflammation, suggesting that increased levels of miR‐378a in psoriatic keratinocytes contribute to the pathogenesis.

To further characterize the molecular mechanism behind this observation, Xia et al. stimulated primary human keratinocytes with psoriasis‐associated cytokines and found IL‐17A to be a strong inducer of miR‐378a. IL‐17A is known to mediate its psoriatic effects by acting on keratinocytes by a mechanism involving intracellular signalling molecules including nuclear factor (NF)‐κB and IκBζ. In line with this, Xia and colleagues reported that the IL‐17A‐induced expression of miR‐378a observed in human keratinocytes was mediated by a mechanism involving NF‐κB, C/EBP‐β and IκBζ.

Interestingly, Xia and colleagues not only demonstrated that IL‐17A activated NF‐κB in keratinocytes, but also reported that overexpression of miR‐378a by itself led to activation of NF‐κB, which was mediated by directly targeting IκBα, a negative regulator of the NF‐κB signalling pathway.

Taking the results together, the study by Xia et al. in a sophisticated manner unravelled a novel mechanism in human keratinocytes where IL‐17A induces miR‐378a, which then acts in a positive feedback loop further amplifying inflammation by activating the NF‐κB signalling pathway. This is an important study because a better understanding of the underlying molecular mechanisms by which IL‐17A mediates its psoriatic effects in human keratinocytes is greatly needed in order to identify new treatment targets. Based on the encouraging results of Xia and colleagues it is possible that modulation of miR‐378a may be a future treatment strategy in inflammatory skin diseases such as psoriasis.