title: Gene from a psoriasis susceptibility locus primes the skin for inflammation.
abstract: 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.
authors.affiliation: Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Wolf
authors.forename: Francesca
authors.initials: F
authors.lastname: Mascia
authors.forename: Alif
authors.initials: A
authors.lastname: Dharamsi
authors.forename: O M Zack
authors.initials: OM
authors.lastname: Howard
authors.forename: Christophe
authors.initials: C
authors.lastname: Cataisson
authors.forename: Val
authors.initials: V
authors.lastname: Bliskovski
authors.forename: Jason
authors.initials: J
authors.lastname: Winston
authors.forename: Lionel
authors.initials: L
authors.lastname: Feigenbaum
authors.forename: Ulrike
authors.initials: U
authors.lastname: Lichti
authors.forename: Thomas
authors.initials: T
authors.lastname: Ruzicka
authors.forename: Triantafyllos
authors.initials: T
authors.lastname: Chavakis
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Yuspa
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D020022:Genetic Predisposition to Disease; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000473:pathology*; D015603:Keratinocytes / Q000166:cytology / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D011565:Psoriasis / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins / Q000235:genetics* / Q000276:immunology; D012867:Skin / Q000276:immunology / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D016207:Cytokines; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins; C089242:S100A7 protein, human; D014409:Tumor Necrosis Factor-alpha