Aberrant production of the IL-17 cytokine, primarily by T helper-17 (Th17) cells, has been implicated in the development of many inflammatory and autoimmune diseases, including, but not limited to Psoriasis, Multiple Sclerosis (MS) and Rheumatoid Arthritis (RA). These and other similarly debilitating diseases associated with this cytokine afflict millions of Americans and cause highly significant economic burdens. IL-17 (IL-17A) and the functionally and structurally closely related IL-17F are the signature cytokines of Th17 cells; they are members of the larger IL-17 cytokine family, which also includes IL-17C and IL-17E (IL-25). IL-25 has been associated with Th2-type responses and, when dysregulated, contributes to the development of Asthma. IL-17A and F are not only produced by Th17 cells, but also by a several innate T cells and by innate lymphocytes type 3 (ILC3s), while IL-25 is produced primarily by epithelial cells. IL-17A and F are particularly important in defense of extracellular bacteria and fungi, while IL-25 is critical in defense of helminths. All IL-17 family cytokines signal via an adaptor protein named CIKS, previously cloned in our laboratory. In the past, we have reported on the functional importance of CIKS/IL-17 cytokines in collagen-induced arthritis (CIA), a mouse model of RA, and in a model of systemic lupus erythematosus (SLE). We discovered that CIKS is essential for development of lupus nephritis, the most fatal form of SLE disease. The latter finding was the first report to clearly implicate a role for IL-17 cytokines in local inflammation in kidneys, i.e. the development of glomerulonephritis. We also identified CIKS as a potential target for therapeutic intervention in psoriasis, a disease that has been closely linked to the actions of the IL-17 cytokine. Mice lacking CIKS were largely protected from the development of imiquimod-induced psoriatic inflammation, a mouse model that closely mimics many aspects of the human disease. We found that IL-17 targeted different cell types to cause the diverse manifestations of the disease. These insights revealed why this cytokine appears to be so central to the development of this disease. In FY2017 we will continue to identify downstream mediators of the inflammatory cascade that initiates with IL-17. In FY2017 we also developed a wound-healing protocol to allow dissection of the role of IL-17 cytokines in this process. We additionally established a skin cancer model to investigate the contributions of this cytokine in tumorigenesis. Previously we reported that the IL-25 cytokine itself was capable of initiating an acute allergic asthma-like lung inflammatory response. In addition to stimulating ILC2s to produce type-2 cytokines IL-13 and IL-5, we discovered that IL-25 mediated some of its effects by targeting dendritic cells in the lung. In addition, we discovered that such treatment led to the production of IL-9 by T cells, another cytokine that has been implicated in asthma. In FY2017 we developed a house dust mite-induced chronic asthma model; house dust mites are critical triggers for allergic asthma in humans as well. This disease model will permit the dissection of unique and redundant roles of IL-25 in the context of an allergen that contains many components and thus leads to activation of many inflammatory pathways. Identification of unique contributions of IL-25 may provide an avenue to pursue therapeutic interventions that target this cytokine in subpopulations of asthma patients that exhibit phenotypes consistent with the pathology promoted by IL-25 in particular.
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