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 FY2018 we identified IL-20 cytokines as critical modulators of imiquimod-induced and IL-17-mediated psoriatic inflammation. IL-20 cytokines constitute a subfamily of IL-10 cytokines that signal via IL-20 receptors. Increased signaling via these receptors during psoriatic inflammation in response to IL-17 cytokines acts to enhance barrier functions and control inflammatory cascades. This insight contrasts with the widely-held view that IL-20 cytokines act downstream of IL-17 to promote pathologic features of psoriasis. In FY2018 we also completed a comprehensive study to evaluate the role of IL-25 in a long-term, chronic house dust mite-induced allergic asthma model. This is a physiologically relevant model, as house dust mites function as major allergens in human asthma; furthermore, this allergen contains multiple components that trigger a variety of inflammatory pathways. Although functions of IL-25 during acute allergic inflammation largely overlap with IL-33, another early alarmin generated during the initiation of inflammation by this allergen, we found IL-25 to make important and unique contributions to the chronic form of allergic asthma, including tissue remodeling, in part via control of specific T helper cells.
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