Gene from a psoriasis susceptibility locus primes the skin for inflammation

• Published in: Science translational medicine 2010-12, Vol.2 (61), p.61ra90-61ra90
• Main Authors: Wolf, Ronald, Mascia, Francesca, Dharamsi, Alif, Howard, O M Zack, Cataisson, Christophe, Bliskovski, Val, Winston, Jason, Feigenbaum, Lionel, Lichti, Ulrike, Ruzicka, Thomas, Chavakis, Triantafyllos, Yuspa, Stuart H
• Format: Article
• Language: English
• Subjects: Animals; Cells, Cultured; Cytokines - immunology; Genetic Predisposition to Disease; Humans; Inflammation - immunology; Inflammation - pathology; Keratinocytes - cytology; Keratinocytes - immunology; Mice; Mice, Transgenic; Psoriasis - genetics; Psoriasis - immunology; Psoriasis - pathology; Receptor for Advanced Glycation End Products; Receptors, Immunologic - metabolism; S100 Calcium Binding Protein A7; S100 Proteins - genetics; S100 Proteins - immunology; Skin - immunology; Skin - pathology; Tumor Necrosis Factor-alpha - immunology
• ISSN: 1946-6234; 1946-6242
• DOI: 10.1126/scitranslmed.3001108

Psoriasis is a common complex genetic disease characterized by hyperplasia and inflammation in the skin; however, the relative contributions of epidermal cells and the immune system to disease pathogenesis remain unclear. Linkage studies have defined a psoriasis susceptibility locus (PSORS4) on 1q21, the epidermal differentiation complex, which includes genes for small S100 calcium-binding proteins. These proteins are involved in extracellular and intracellular signaling during epithelial host defense, linking innate and adaptive immunity. Inflammation-prone psoriatic skin constitutively expresses elevated concentrations of S100A7 (psoriasin) and S100A15 (koebnerisin) in the epidermis. Here, we report that genetically modified mice expressing elevated amounts of doxycycline-regulated mS100a7a15 in skin keratinocytes demonstrated an exaggerated inflammatory response when challenged by exogenous stimuli such as abrasion (Koebner phenomenon). This immune response was characterized by immune cell infiltration and elevated concentrations of T helper 1 (T(H)1) and T(H)17 proinflammatory cytokines, which have been linked to the pathogenesis of psoriasis and were further amplified upon challenge. Both inflammation priming and amplification required mS100a7a15 binding to the receptor of advanced glycation end products (RAGE). mS100a7a15 potentiated inflammation by acting directly as a chemoattractant for leukocytes, further increasing the number of inflammatory cells infiltrating the skin. This study provides a pathogenetic psoriasis model using a psoriasis candidate gene to link the epidermis and innate immune system in inflammation priming, highlighting the S100A7A15-RAGE axis as a potential therapeutic target.