Excessive Polyamine Generation in Keratinocytes Promotes Self-RNA Sensing by Dendritic Cells in Psoriasis

• Published in: Immunity (Cambridge, Mass.) Vol. 53; no. 1; pp. 204 - 216.e10
• Main Authors: Lou, Fangzhou, Sun, Yang, Xu, Zhenyao, Niu, Liman, Wang, Zhikai, Deng, Siyu, Liu, Zhaoyuan, Zhou, Hong, Bai, Jing, Yin, Qianqian, Cai, Xiaojie, Sun, Libo, Wang, Hong, Li, Qun, Wu, Zhouwei, Chen, Xiang, Gu, Jun, Shi, Yu-Ling, Tao, Wufan, Ginhoux, Florent, Wang, Honglin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.07.2020; Elsevier Limited
• Subjects: 3T3 Cells; Ablation; Animal models; Animals; ARG1; Arginase; Arginase - antagonists & inhibitors; Arginase - metabolism; Arginine - metabolism; Autoantigens - immunology; CCAAT-Enhancer-Binding Protein-beta - metabolism; CCAAT/enhancer-binding protein; Cell cycle; Cell Line; Dendritic cells; Dendritic Cells - immunology; Deregulation; Disease Models, Animal; Endocytosis; Etiology; Gene expression; HaCaT Cells; HEK293 Cells; Humans; Hyperplasia; Hyperreactivity; Hypersensitivity; Inflammation; Inflammatory diseases; Interleukin 17; Interleukin 6; Interleukin-17 - metabolism; Keratin; Keratinocytes; Keratinocytes - metabolism; Macaca fascicularis; Membrane Glycoproteins - immunology; Metabolism; Metabolites; Mice; Mice, Inbred C57BL; MicroRNAs; Phosphoprotein Phosphatases - deficiency; Phosphoprotein Phosphatases - genetics; Phosphorylation; Polyamines; Polyamines - metabolism; Protein phosphatase; Protein Phosphatase 6 (PP6); Psoriasis; Psoriasis - pathology; Ribonucleic acid; RNA; RNA - immunology; self-RNA; Skin; Skin - pathology; TLR7 protein; Toll-Like Receptor 7 - immunology; Toll-like receptors; Transcription activation; Tumor necrosis factor-TNF; Urea; urea cycle; dendritic cells; ARG1; psoriasis; keratinocytes; urea cycle; polyamines; Protein Phosphatase 6 (PP6); arginase; self-RNA
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2020.06.004

Psoriasis is a chronic inflammatory disease whose etiology is multifactorial. The contributions of cellular metabolism to psoriasis are unclear. Here, we report that interleukin-17 (IL-17) downregulated Protein Phosphatase 6 (PP6) in psoriatic keratinocytes, causing phosphorylation and activation of the transcription factor C/EBP-β and subsequent generation of arginase-1. Mice lacking Pp6 in keratinocytes were predisposed to psoriasis-like skin inflammation. Accumulation of arginase-1 in Pp6-deficient keratinocytes drove polyamine production from the urea cycle. Polyamines protected self-RNA released by psoriatic keratinocytes from degradation and facilitated the endocytosis of self-RNA by myeloid dendritic cells to promote toll-like receptor-7 (TLR7)-dependent RNA sensing and IL-6 production. An arginase inhibitor improved skin inflammation in murine and non-human primate models of psoriasis. Our findings suggest that urea cycle hyperreactivity and excessive polyamine generation in psoriatic keratinocytes promote self-RNA sensation and PP6 deregulation in keratinocytes is a pivotal event that amplifies the inflammatory circuits in psoriasis. [Display omitted] •Pp6 deficiency in keratinocytes predisposes psoriasis-like skin disease•PP6 deficiency in keratinocytes promotes ARG1-facilitated polyamine generation•Together with cargo peptides, polyamines promote endosomal self-RNA sensing by DCs•An arginase inhibitor alleviates psoriasis-like skin disease in mice and monkeys Psoriasis is an incurable chronic skin inflammatory disorder associated with metabolic abnormalities, but the causes and consequences of such metabolic alterations remain unclear. Lou et al. report that PP6 deficiency in psoriatic epidermis leads to hyperreactive arginine metabolism, which promotes dendritic cell activation and release of pro-inflammatory cytokines.