Cross-talk between IFN-γ and TWEAK through miR-149 amplifies skin inflammation in psoriasis

Background: Psoriasis is a chronic inflammatory skin disease with disturbed interplay between immune cells and keratinocytes. A strong IFN-gamma signature is characteristic for psoriasis skin, but the role of IFN-gamma has been elusive. MicroRNAs are short RNAs regulating gene expression. Objective: Our aim was to investigate the role of miR-149 in psoriasis and in the inflammatory responses of keratinocytes. Methods: miR-149 expression was measured by quantitative RT-PCR in keratinocytes isolated from healthy skin and lesional and nonlesional psoriasis skin. Synthetic miR-149 was injected intradermally into the back skin of mice, and imiquimod was applied to induce psoriasis-like skin inflammation, which was then evaluated at the morphologic, histologic, and molecular levels. miR-149 was transiently overexpressed or inhibited in keratinocytes in combination with IFN-gamma- and/or TNF-related weak inducer of apoptosis (TWEAK)-treatment. Results: Here we report a microRNA-mediated mechanism by which IFN-gamma primes keratinocytes to inflammatory stimuli. Treatment with IFN-gamma results in a rapid and long-lasting suppression of miR-149 in keratinocytes. Depletion of miR-149 in keratinocytes leads to widespread transcriptomic changes and induction of inflammatory mediators with enrichment of the TWEAK pathway. We show that IFN-gamma-mediated suppression of miR-149 leads to amplified inflammatory responses to TWEAK. TWEAK receptor (TWEAKR/Fn14) is identified as a novel direct target of miR-149. The in vivo relevance of this pathway is supported by decreased miR-149 expression in psoriasis keratinocytes, as well as by the protective effect of synthetic miR-149 in the imiquimod-induced mouse model of psoriasis. Conclusion: Our data define a new mechanism, in which IFN-gamma primes keratinocytes for TWEAK-induced inflammatory responses through suppression of miR-149, promoting skin inflammation.

Automated summary

IFN-γ suppresses miR-149 to prime keratinocytes for inflammatory responses, leading to skin inflammation.