P3:VEGF Influences Keratinocyte-Immunocyte Interactions in Psoriasiform Dermatiti

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Psoriasis is a common, chronic skin disease characterized by recurrent erythematous skin plaques that exhibit epidermal hyperplasia, inflammatory cell accumulation, and abnormalities of the papillary dermal vasculature. Studies examining the role of vascular specific growth factors have shown that members of the vascular endothelial growth factor (VEGF) and angiopoietin families contribute significantly to the development and maintenance of the psoriasis phenotype. We have engineered a line of mice that overexpress the angiopoietin tyrosine kinase receptor, Tie2 in keratinocytes (KCs), and our preliminary data suggests that these mice have a psoriasiform phenotype, including significant increases in endogenous VEGF, presence of acanthotic, erythematous skin, increased angiogenesis, and increased inflammatory cell infiltration, specifically neutrophils and myeloid/monocytic cells. We hypothesize that KC-specific tyrosine kinase receptor overexpression leads to KC proliferation, via increased VEGF expression and activation. This cutaneous change leads to increased angiogenesis, leaky vessels, and induction of the proinflammatory protein, S100A8/9, all of which enhance monocyte/myeloid cell recruitment, activation, and inflammation which maintain the psoriasiform phenotype. Using a combination of mouse molecular genetic approaches and function blocking antibodies, we will inhibit VEGF signaling, S100A8/A9 expression, or eliminate macrophages and determine the effects on the development and/or resolution of the phenotype. The information from these studies will provide further understanding about the roles, interactions, and significance of VEGF, S100A8/A9 and monocytic/myeloid cell activation in the development and maintenance of the psoriatic environment and could result in the identification of new therapeutic targets.