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 FY2019 we identified the IL-19 and, to a lesser extent, IL-24 as cytokines that acted as critical modulators of imiquimod-induced and IL-17-mediated psoriatic inflammation. Along with IL-20, these cytokines are part of the IL-20 family, which itself is part of the IL-10 superfamily. IL-20 cytokines signal via IL-20 receptors IL-20RI (IL-20RA/RB, engaged by IL-19, IL-20 and IL-24) and IL-20RII (IL-20RB/IL-22RA1, engaged by IL-20 and IL-24). We show that IL-20 receptor signaling, especially in response to IL-19, ameliorates psoriatic inflammation. This insight goes against the previous prevailing, alas unproven view that IL-19 is part of the pathologic sequelae of IL-17. Instead IL-19 reduces chemokine-induced accumulation of inflammatory cell infiltrates in the dermis, including in particular IL-17-producing gamma-delta T cells. This constitutes a negative feedback, since IL-17 strongly induces IL-19 in keratinocytes. IL-19 ameliorates psoriatic inflammation in the dermis in part by suppressing expression of CCL2 in skin; CCL2 is the primary ligand for CCR2 and attracts monocytes, neutrophils and recruits dermal gamma-delta T cells into skin from sDLNs, specifically under inflammatory conditions. In FY2019 we also determined that IL-25 is critical for chronic (long-term) house dust mite (HCM)-induced allergic asthma pathology, even though its functions were thought to be redundant with those of TSLP and IL-33, two other type-2-promoting cytokines induced by HDM. IL-25 greatly contributed to neutrophil infiltration, as well as to production of IL-13 and especially of IL-9, two type-2 cytokines. In consequence, IL-25 contributed notably to mast cell accumulation, collagen-deposition (tissue remodeling) and lung function. We found that IL-25 targeted conventional dendritic cells to produce mediators such as CCL17 to attract Th2 and Th9 cells, which were then also directly targeted by IL-25 to produce IL-13 and especially IL-9, respectively. This demonstrates that the so-called alarmin has critical roles as a promoter of adaptive type-2 immune responses in allergic asthma.

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Das, Nitin A; Carpenter, Andrea J; Yoshida, Tadashi et al. (2018) TRAF3IP2 mediates TWEAK/TWEAKR-induced pro-fibrotic responses in cultured cardiac fibroblasts and the heart. J Mol Cell Cardiol 121:107-123
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Yariswamy, Manjunath; Yoshida, Tadashi; Valente, Anthony J et al. (2016) Cardiac-restricted Overexpression of TRAF3 Interacting Protein 2 (TRAF3IP2) Results in Spontaneous Development of Myocardial Hypertrophy, Fibrosis, and Dysfunction. J Biol Chem 291:19425-36
Sakamuri, Siva Sankara Vara Prasad; Higashi, Yusuke; Sukhanov, Sergiy et al. (2016) TRAF3IP2 mediates atherosclerotic plaque development and vulnerability in ApoE(-/-) mice. Atherosclerosis 252:153-160

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