! ! ! IL-17 and Th17 cells drive pathology in a variety of autoimmune and pathologic inflammatory conditions. Recently, biologic drugs targeting the IL-17 pathway have shown clinical efficacy in psoriasis, and are under evaluation for other autoimmune and inflammatory disease conditions. We have a long-standing interest in understanding the fundamental basis for IL-17 signaling, with the premise that defining the molecular mediators of disease pathology will ultimately help lead to development of the most effective or specific therapeutic targets, diagnostics or biomarkers. IL-17 regulates downstream inflammatory genes by transcriptional mechanisms, mainly involving the canonical NF-?B pathway as well as CCAAT/Enhancer binding proteins (C/EBPs). IL-17 also activates numerous post-transcriptional mechanisms that control mRNA stability and translation. In a screen to identify new intermediates involved in IL-17-dependent downstream signaling, we discovered that IL-17 induces a novel RNA binding protein (RBP) that was never previously linked to IL-17 signaling, T cells or autoimmune pathology. Strikingly, cells lacking this RBP exhibited markedly impaired in IL-17 signaling, especially activation of NF-?B and C/EBP?. In vivo, mice lacking this RBP were refractory to IL-17-driven inflammatory diseases, including experimental autoimmune encephalomyelitis (EAE), a model of MS, and AGN, a model of autoimmune glomerulonephritis. The goals of this application are to define the mechanisms by which this novel RBP pathway controls IL-17-dependent signal transduction (Aim 1) and the tissue-specific consequences to IL-17-induced autoimmune pathology using EAE as a model system (Aim 2). !
The immune system maintains a careful balance between protecting the body from infectious pathogens and the collateral damage that may arise as a result of too much inflammation, particularly autoimmunity. Interleukin (IL)-17 is an important mediator of immune inflammation and protects against various microorganisms. However, an overabundance of IL-17 signaling contributes to the pathogenesis of autoimmunity. Antibodies that block IL-17 are now approved for psoriasis, but this treatment may put patients at risk for developing infections. Although we know quite a bit about which cells make IL-17, the molecular process of IL-17 signaling through its receptor is poorly defined. This proposal focuses on how the regulation of IL-17-driven mRNA expression occurs at a molecular level and how this serves to control autoimmune pathology. !
