343 Endogenous double-stranded RNA is a potential target for psoriasis therapy

Abstract

The activation of endogenous double-stranded RNA (endo-dsRNA) signalling pathways is linked to a variety of autoimmune diseases. Here, we investigated the role of endogenous dsRNA in psoriasis by quantifying dsRNA binding protein (DRBP) mRNA and mitochondrial dsRNA formation in response to narrow-band UVB (NB-UVB) treatment. RNAseq data from 34 psoriatic patients treated with NB-UVB were analysed. Biopsies were obtained from four sites 24h after NB-UVB irradiation (lesional unirradiated, nonlesional unirradiated lesional irradiated with one minimal erythemal dose (MED), lesional irradiated with three MEDs. Psoriatic lesional skin had a significantly higher expression of all examined DRBP (RIG, MDA5, LGP2, PKR, OAS1-3, OASL) as compared to nonlesional skin (increase between 1.5-21.7 fold, p <0.001 for all eight genes). NB-UVB treatment had no effect on the DRBPs after 24h of one or three MEDs of NB-UVB. Additionally, a significant reduction (about 20%) of dsRNA from mitochondrial transcripts was detected in response to both NB-UVB doses(p-value 0.012 and 0.001, respectively). These results indicate that increased levels of dsRNA activate RIG, MDA5, and LGP2 in lesional compared to nonlesional psoriasis skin. RIG, MDA5, and LGP2 in turn upregulate type1 IFN via recruiting TBK1, and IRF3/7, all of which were significantly upregulated in the lesional unirradiated skin. PKR binds endo-dsRNA, and activation of PKR enhances IFN-α/β expression via IRF3. Moreover, OASs trigger an antiviral response via a RIG induced IFN pathway. Once activated, IFN strongly enhances the transcription of DRBP thus creating a vicious cycle that exacerbates the immune response. In conclusion, upregulation of all DRBP genes in psoriatic lesional skin indicates that endo-dsRNA may play a crucial role in psoriasis pathogenesis, and the early reduction of the mitochondrial dsRNA after NB-UVB treatment suggests that dsRNA is an important target for psoriasis therapy.