Keratinocyte Metabolic Reprogramming Promotes Self-RNA Sensation In Psoriasis

The maintenance of psoriasis as a skin-confined chronic inflammatory condition requires the abnormal interplay between hyperproliferative epidermal keratinocytes and self-reactive immune cells[1].In this context,targeting metabolism of keratinocytes is recently reported to be an approach for treating psoriasis[2],however whether and how the metabolic adaptations of keratinocytes introduce inflammatory cues are unknown.We report that in psoriatic lesions,Protein Phosphatase 6(PP6)is targeted by microRNA(miR)-31 and is diminished in the epidermis,and its levels negatively correlate with the disease severity.Mice with genetic deficiency of Pp6 in keratinocytes spontaneously develop psoriasis-like skin phenotype resembling psoriasis clinically,histologically,in its gene expression profile and in its response to therapy.Mechanistically,Pp6-/-keratinocytes rely on inordinate urea cycle along with enhanced oxidative phosphorylation(OXPHOS)to hyper-proliferate,mediated by increased Arginase-1(Arg1)production resulting from the activation of CCAAT/enhancer-binding protein beta(C/EBP?).Single-cell RNA-seq reveals the Arginine biosynthesis rate-limiting enzyme,Argininosuccinate synthetase 1(ASS1),maintains the pool of Arginine in psoriatic epidermis.Moreover,accumulated polyamines branched from urea cycle promote self-RNA sensing by myeloid dendritic cells with the assistance of an RNA-binding peptide originated from heterogeneous nuclear ribonucleoprotein A1(HNRNPA1),a probable autoantigen in psoriasis[3],which directly links keratinocyte hyperproliferation to autoimmune responses.Targeting metabolic nodes of urea cycle in imiquimod-induced mouse and non-human primate models of psoriasis markedly improves the skin inflammation.Thus,our data reveal for the first time the molecular basis of an auto-inflammatory condition and the functional significance of target organ-intrinsic metabolic reprogramming in inflammation,bringing forth novel insights into the pathogenesis and therapeutic strategies of chronic inflammatory disorders.