Epigenetic Regulation of IL-23 by E3 Ligase FBXW7 in Dendritic Cells Is Critical for Psoriasis-like Inflammation

Abstract

Dendritic cells (DCs), a driver of psoriasis pathogenesis, produce IL-23 and trigger IL-23/IL-17 cytokine axis activation. However, the mechanisms regulating IL-23 induction remain unclear. In the current study, we found that mice with E3 ligase FBXW7 deficiency in DCs show reduced skin inflammation correlated with the reduction of IL-23/IL-17 axis cytokines in the imiquimod-induced psoriasis model. Fbxw7 deficiency results in decreased production of IL-23 in DCs. FBXW7 interacts with the lysine N-methyltransferase suppressor of variegation 39 homolog 2 (SUV39H2), which catalyzes the trimethylation of histone H3 Lys9 (H3K9) during transcription regulation. FBXW7 mediates the ubiquitination and degradation of SUV39H2, thus decreasing H3K9m3 deposition on the Il23a promoter. The Suv39h2 knockout mice displayed exacerbated skin inflammation with the IL-23/IL-17 axis overactivating in the psoriasis model. Taken together, our results indicate that FBXW7 increases IL-23 expression in DCs by degrading SUV39H2, thereby aggravating psoriasis-like inflammation. Inhibition of FBXW7 or the FBXW7/SUV39H2/IL-23 axis may represent a novel therapeutic approach to psoriasis.