Molecular Mechanisms of IL-17-dependent autoimmune signaling

IL-17和Th17细胞在多种自身免疫性和病理性疾病中的作用 炎症状态。最近，针对IL-17途径的生物药物已经 已显示出对银屑病的临床疗效，并正在评估其他自身免疫性和 炎症性疾病状况。我们长期以来一直有兴趣了解 IL-17信号的基本基础，前提是定义分子 疾病病理的介体最终将有助于大多数 有效或特定的治疗靶点、诊断或生物标志物。IL-17调节 下游的炎症基因通过转录机制，主要涉及 典型的NF-κB途径以及CCAAT/增强子结合蛋白(C/EBPs)。IL-17 也激活了许多控制mRNA稳定性的转录后机制 还有翻译。在屏幕上识别参与IL-17依赖的新中间体 在下游信号传递过程中，我们发现IL-17诱导了一种新的RNA结合蛋白 (RBP)以前从未与IL-17信号、T细胞或自身免疫有关 病理学。值得注意的是，缺乏这种RBP的细胞在IL-17中表现出明显的损伤 信号转导，尤其是核因子-κB和C/EBPδ的激活。在体内，缺乏这种RBP的小鼠 对IL-17驱动的炎症性疾病无效，包括实验性 自身免疫性脑脊髓炎(EAE)是MS的模型，AGN是MS的模型 自身免疫性肾炎。此应用程序的目标是定义 这一新的RBP途径控制IL-17依赖信号的机制 转导(AIM 1)与IL-17诱导的自身免疫的组织特异性后果 以EAE为模型系统的病理学(目标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).