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.

Public Health Relevance

Currently ~2-3% of the American population suffers from the inflammatory skin disease, psoriasis, with the socioeconomic costs being highly significant. Despite the prevalence of this disease, the cause of psoriasis remains unknown, and despite interventions resulting in clinical resolution of the disease, durable remission and/or cure has no been achieved. Current psoriasis therapies are directed towards sign/symptom relief;however many of the most effective therapeutics also have the greatest adverse reactions, therefore an ongoing need for discovery of novel biological targets and subsequent therapeutics exists. Understanding the cellular and molecular mechanisms by which IL-17C promotes cutaneous inflammation in psoriasis will provide insight into IL-17C-mediated amplification of Th17/22/TNFa mediated inflammatory signaling, and may identify IL-17C as a novel target for the development of therapeutic strategies.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
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Arthritis, Connective Tissue and Skin Study Section (ACTS)
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Cibotti, Ricardo
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Case Western Reserve University
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Swindell, William R; Beamer, Maria A; Sarkar, Mrinal K et al. (2018) RNA-Seq Analysis of IL-1B and IL-36 Responses in Epidermal Keratinocytes Identifies a Shared MyD88-Dependent Gene Signature. Front Immunol 9:80
Monin, Leticia; Gaffen, Sarah L (2018) Interleukin 17 Family Cytokines: Signaling Mechanisms, Biological Activities, and Therapeutic Implications. Cold Spring Harb Perspect Biol 10:
Swindell, William R; Sarkar, Mrinal K; Liang, Yun et al. (2017) RNA-seq identifies a diminished differentiation gene signature in primary monolayer keratinocytes grown from lesional and uninvolved psoriatic skin. Sci Rep 7:18045
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Wang, QuanQiu; McCormick, Thomas S; Ward, Nicole L et al. (2017) Combining mechanism-based prediction with patient-based profiling for psoriasis metabolomics biomarker discovery. AMIA Annu Symp Proc 2017:1734-1743
Fritz, Yi; Klenotic, Philip A; Swindell, William R et al. (2017) Induction of Alternative Proinflammatory Cytokines Accounts for Sustained Psoriasiform Skin Inflammation in IL-17C+IL-6KO Mice. J Invest Dermatol 137:696-705
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