Psoriasis is a chronic inflammatory skin disease with disturbed interplay between immune cells and keratinocytes. Here we identify a microRNA-mediated mechanism by which IFN-γ primes keratinocytes to inflammatory stimuli. Treatment with IFN-γ results in a quick and long-lasting suppression of miR-149 in keratinocytes. Depletion of miR-149 in keratinocytes results in wide-spread transcriptomic changes and induction of inflammatory mediators with an enrichment of the TWEAK-pathway. We demonstrate that IFN-γ primes keratinocytes to TWEAK-induced IL-6 expression and this is mediated by suppression of miR-149. TWEAK receptor (TWEAKR) is identified as a novel direct target of miR-149. The in vivo relevance of this pathway is supported by decreased miR-149 and increased TWEAKR expression in psoriasis keratinocytes, as well as by the protective effect of synthetic miR-149 in the imiquimod-induced mouse model of psoriasis. Mice with keratinocyte-specific deletion of miR-149 been generated and our preliminary results show that these mice display increased severity of skin inflammation in the imiquimod-induced mouse model of psoriasis. Altogether, our data define a new mechanism, in which IFN-γ primes keratinocytes for TWEAK-induced inflammatory responses through suppression of miR-149, which leads to enhanced skin inflammation in psoriasis.

ESDR211 - IFN-γ enhances TWEAK-induced inflammatory responses in psoriasis keratinocytes through suppression of miR-149

50th Annual Meeting of the European Society for Dermatological Research. VIRTUAL MEETING