Gene from a Psoriasis Susceptibility Locus Primes the Skin for Inflammation

Psoriasis candidate genes promote susceptibility to skin inflammation and provide a treatment approach for psoriasis-related inflammation. Tipping the Scales Fashion models and the masses alike crave flawless skin achieved without the help of Photoshop. Yet, for sufferers of psoriasis, an autoimmune disease of the skin, this dream is far out of reach. Psoriasis, which frequently manifests as red or white scaly plaques on the skin, currently has no cure, although the symptoms may be treated by inhibiting either T cells or inflammatory cytokines. Wolf et al. bring us one step closer to a cure by fashioning a mouse model that mimics psoriasis in patients and can be used to develop therapies for the disease. Both immune cells and epidermal cells of the skin contribute to pathogenesis in psoriatic lesions; however, the relative contribution of these systems to disease development remains unknown. To investigate this contribution, Wolf et al. generated a mouse model of psoriasis by conditionally overexpressing the inflammation-associated protein mS100a7a15 in keratinocytes. The related human S100A7 and S100A15 proteins are encoded in a psoriasis susceptibility locus and are involved in cellular signaling during epithelial host defense. This new mouse model is especially relevant to the human disease because the human homologs of mS100a7a15 (hS100A7/S100A15) are overexpressed in the epidermis of inflammatory lesions from psoriasis patients. The model by Wolf et al. mimicked the disease in humans, inducing an inflammatory response after abrasion that consisted of elevated amounts of proinflammatory T cells and cytokines. These effects were mediated by the mS100a7a15 receptor RAGE (receptor of advanced glycation end products), suggesting the S100a7a15-RAGE axis as a therapeutic target for psoriasis. Thus, this model not only links the epidermal and immune contributions of psoriasis but also may tip the scales toward fewer scales (and flawless skin) for psoriasis patients. 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 (TH1) and TH17 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.