IL-17C is a novel and functionally distinct member of the IL-17 family of cytokines and acts through IL- 17RE and IL-17RA to promote innate defense in epithelial cells and regulate Th17 cell differentiation. In human psoriasis tissue, IL-17C is highly expressed in lesional skin and localizes to and exerts effects upon keratinocytes (KCs), endothelial cell (ECs) and leukocytes. Our preliminary data demonstrates increases in CD4+ T cell-derived IL-17A and IL-22 (Th17 and Th22) and EC-derived TNFa following IL-17C stimulation. Interestingly, KCs stimulated with IL-17C and TNF produce similar synergistic inflammatory gene response patterns as those elicited by IL-17A/TNF (but at higher magnitudes) and these gene response patterns are further enhanced with the addition of IL-17A, indicating a positive pro-inflammatory feedback loop between the endothelium, epidermis and Th17/22 cells. In psoriasis patients treated with TNFa inhibitors, cutaneous IL-17C expression decreases rapidly (within 72h) prior to skin improvement and decreases in serum levels of IL-17A and IL-22 suggesting IL-17C may serve as a novel mechanism for amplifying Th17/22/TNFa mediated inflammatory signaling critical for psoriasis pathogenesis. To further explore the importance of IL-17C in mediating psoriasiform inflammation, we genetically engineered mice to overexpress IL-17C in KCs. Murine skin develops well demarcated areas of uninvolved tissue, characterized by increased angiogenesis and modest leukocyte infiltration in the absence of epidermal hyperplasia as well as adjacent areas of involved skin that exhibit robust epidermal hyperplasia, increased leukocyte infiltration and increases in TNFa, IL-17A, and IL-22; suggesting that IL-17C, when coupled with other pro-inflammatory signals, leads to the development of psoriasiform skin dermatitis. Taken together, these observations suggest that IL-17C is a rapidly responsive member of the IL-17 family and that it synergistically activates a proinflammatory feedback loop between KCs, the endothelium and Th17/22 cells and may be critical in psoriasis. We will use this innovative new mouse model, genetic knockout approaches, cre-lox technologies and antibody targeting strategies coupled with in vitro cell co-culture, SiRNA, cell signaling and bioassay approaches to test the hypothesis that: IL-17C binding IL-17RE/A on target cells up regulates TNF (EC) and IL-17/IL-22 (Th17/22) that combine synergistically with IL-17C to induce KC activation and epidermal hyperplasia. We intend to identify IL-17C as a critical early upstream proinflammatory cytokine required for initiating and sustaining chronic skin inflammation, and identify the key cellular targets affected by IL-17C as well as the potential mechanism(s) used to direct KC, EC and Th17/22 cell responses that translate to sustaining inflammation and acanthosis in psoriasis. This work will provide the basis and justification for future work exploring the potential of targeting IL-17C or IL-17RE for therapeutic development for the treatment of psoriasis.