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

Abstract

34 35 2 1 SUMMARY 2 3The mechanisms underlying tissue-specific chronic inflammation are elusive. Here we 4 report that mice lacking Protein Phosphatase 6 in keratinocytes are predisposed to 5 psoriasis-like skin inflammation, with an inordinate urea cycle and enhanced oxidative 6 phosphorylation that supports hyperproliferation. This phenotype is mediated by 7 increased Arginase-1 production resulting from CCAAT/enhancer-binding protein beta 8 activation. Single-cell RNA-seq of the psoriatic epidermis revealed that the 9 rate-limiting enzyme for Arginine biosynthesis, Argininosuccinate synthetase 1, 10 maintains the Arginine pool, which is indispensable for immune responses. 11 Accumulated polyamines branched from the urea cycle promote endosomal 12 Tlr7-dependent self-RNA sensing by myeloid dendritic cells. This process is achieved 13 with the assistance of an RNA-binding peptide that originates from the heterogeneous 14 nuclear ribonucleoprotein A1, a probable autoantigen in psoriasis. Finally, targeting 15 urea cycle wiring with an arginase inhibitor markedly improved skin inflammation in 16 murine and non-human primate models of psoriasis. Our findings suggest that urea 17 cycle alteration and excessive polyamine production by psoriatic keratinocytes 18 promote self-RNA sensing by dendritic cells, which links the hyperproliferation of 19 stationary cells with innate-immune activation in an auto-inflammatory condition. 20 21 3 1 12 Ganguly et al., 2009), understanding how these RNA-binding proteins are handled by 13 antigen-presenting cells before they become recognized by self-reactive T cells 14 should be addressed. 15 16We previously reported that a microRNA directly targets Protein Phosphatase 6 (PP6) 17 as a negative cell cycle regulator in psoriatic keratinocytes (Yan et al., 2015). PP6, 18 which consists of one catalytic subunit and two regulatory subunits, is crucial for skin 19 homeostasis (Bonilla et al., 2016; Hodis et al., 2012; Krauthammer et al., 2012). 20 Given the versatility of serine/threonine phosphatases, we aimed to determine the 21 specific functionality of PP6 in keratinocytes. Using a genetic ablation approach, we 6 1 RESULTS 2 3 Epidermis-specific Pp6-deficient mice spontaneously develop psoriasis-like skin 4 inflammation 5 We previously found that PP6 is directly targeted by microRNA-31, one of the most 6 highly overexpressed microRNAs in human psoriatic skin (Xu et al., 2013; Yan et al., 7 2015). We first performed an immunohistochemical analysis of PP6 on skin sections 8 derived from five healthy donors and 117 patients with psoriasis. We found that PP6 9 was ubiquitously expressed in all epidermal layers of the healthy skin but was 10 comparatively reduced in psoriatic lesions (Figure S1A). Notably, we detected a 11 strong negative correlation between PP6 levels and epidermal hyperplasia (Figure 12 S1B). When correlating the Psoriasis Area and Severity Index (PASI) and the PP6 13 expression levels, we found that epidermal PP6 levels in the severe group (PASI > 20) 14 w...