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.