990 Targeting metabolism reprogramming of keratinocytes improves psoriasis-like skin inflammation

Abstract

Keratinocyte-intrinsic metabolic reprogramming is the major fuel to epidermal hyperplasia in psoriasis, yet the underlying cause is poorly understood. We report that in psoriatic lesions, Protein Phosphatase 6 (PP6) 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 ornithine cycle and 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/EBPβ) and elevated levels of mitochondrial respiration chain components. Treating imiquimod-induced mouse model of psoriasis with an arginase inhibitor or (and) an OXPHOS inhibitor markedly improves the skin inflammation. Thus, our data reveal for the first time the molecular basis and the functional significance of keratinocyte metabolic adaptations in psoriasis, bringing forth novel therapeutic strategies targeting keratinocyte metabolism to treat psoriasis.