Molecular Mechanisms of IL-17-dependent autoimmune signaling

IL-17和Th 17细胞在多种自身免疫和病理性免疫反应中驱动病理。 炎性条件。最近，靶向IL-17通路的生物药物已经 在银屑病中显示出临床疗效，并正在评估其他自身免疫性疾病， 炎症性疾病状况。我们长期以来一直有兴趣了解 IL-17信号传导的基本基础，前提是定义分子 疾病病理学的介质最终将有助于导致最 有效或特异的治疗靶点、诊断或生物标志物。IL-17调节 下游炎症基因的转录机制，主要涉及 典型的NF-κB途径以及CCAAT/增强子结合蛋白（C/EBP）。IL-17 还激活许多控制mRNA稳定性的转录后机制 和翻译。在筛选以鉴定参与IL-17依赖性免疫应答的新中间体中， 下游信号，我们发现IL-17诱导一种新的RNA结合蛋白， (RBP)以前从未与IL-17信号传导，T细胞或自身免疫相关 病理令人惊讶的是，缺乏这种RBP的细胞在IL-17 信号转导，尤其是NF-κB和C/EBPδ的活化。在体内，缺乏这种RBP的小鼠 对IL-17驱动的炎症性疾病，包括实验性 自身免疫性脑脊髓炎（EAE），MS的模型，和AGN，MS的模型， 自身免疫性肾小球肾炎此应用程序的目标是定义 这种新的RBP途径控制IL-17依赖性信号的机制 转导（目的1）和组织特异性后果，以IL-17诱导的自身免疫性 使用EAE作为模型系统的病理学（Aim 2）。

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-κB 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-κB and C/EBPδ. 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).