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 in collagen-induced arthritis (CIA), a mouse model of RA, and in a model of systemic lupus erythematosus (SLE). We discovered that CIKS was 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 FY 2016 we elucidated a new mechanisms by which the IL-25 cytokine can promote asthma-like allergic lung inflammation. Previously IL-25 was known to contribute to inflammation by stimulating ILC2s to produce the type-2 cytokines IL-13 and IL-5, but we discovered that IL-25 was also able to target dendritic cells. This in led to production of in particular chemokines known to attract Th2 and Th9 cells. Th9 cells were rapidly recruited to produce IL-9, a cytokine also clearly implicated in asthma. We showed that IL-25 stimulation of dendritic cells also mediated production of IL-9 by T cells in the context of house dust mite challenge, a physiologically relevant model for human asthma. These insights reveal a novel pathway involved in lung inflammation.
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