LB1050 Qing-Re Chu-Shi Decoction Improves 2,4-dinitrochlorobenzene-induced Atopic Dermatitis-like Skin Lesions via Anti-inflammatory and Immune Regulation

Abstract

The maintenance of psoriasis as a skin-confined chronic inflammatory condition requires the abnormal interplay between hyperproliferative epidermal keratinocytes and self-reactive immune cells. In this context, targeting metabolism of keratinocytes is recently reported to be an approach for treating psoriasis, 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 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/EBPb). 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, 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.