IL-17C-IL-17RE信号通路在炎症性疾病中的作用机制

IL-17A has been shown to play a critical role in the pathogenesis of variety of inflammatory disorders including autoimmune diseases. Targeting IL-17A or its receptor holds great promising in the therapy of autoimmune diseases. We recently discovered the function of IL-17C, a previously uncharacterized member of IL-17 cytokine family. IL-17C associates with IL-17RE (an orphan receptor) and IL-17RA (a shared receptor) to activate down-stream signaling and induce production of pro-inflammatory genes, and plays an important role in host mucosal immunity against infections. Our preliminary results also showed that IL-17C critically regulated the pathogenesis of autoimmune diseases. As the pairing of IL-17C and its receptor IL-17RE has just recently been discovered, the signaling and functional mechanism of this IL-17C-IL-17RE pathway in the pathogenesis of inflammatory autoimmune diseases is largely unknown. This grant is proposed to investigate the signaling mechanism of the new pathway, screen for new signaling molecules, and demonstrate the functional mechanisms of this pathway in the pathogenesis of autoimmune diseases. The grant also plans to target the IL-17C-IL-17RE pathway through the soluble receptor of IL-17RE to study its therapeutic effect on the pathogenesis of autoimmune diseases. Furthermore, the grant plans to compare the function and signaling of IL-17C with those of IL-17A in the pathogenesis of autoimmune diseases for similarity and difference. The aims of the proposal are to find new therapeutic targets and provide new information for targeting strategies for inflammatory autoimmune diseases.

IL-17A参与多种炎症性疾病如自身免疫病的病理，已成为相关疾病的治疗靶标。我们最近首次发现了IL-17C的功能，它通过结合特异性受体IL-17RE及该家族中共享受体IL-17RA，诱导炎症性基因的表达，参与宿主肠道抗感染免疫。我们的预实验结果也显示该通路参与调控炎症性自身免疫病的病理。由于IL-17C-IL-17RE的配对及其功能才刚刚被揭开，这条信号通路中的转导机制还是研究空白，并且其参与炎症性疾病病理的机制还不清楚。本申请拟研究IL-17C-IL-17RE通路的信号转导机制，筛选新的信号分子，阐明其在炎症性自身免疫病中的功能与作用机制，并通过可溶性受体靶向该通路探讨其在自身免疫病中的治疗作用。同时与IL-17A的功能与作用机制做对比，阐明IL-17C与IL-17A在信号转导及炎症性疾病病理机制中的异同。这些原创性研究将为相关炎症性疾病的治疗提供重要的理论基础、新靶标与新策略。

我们的前期工作发现IL-17C的特异性受体是IL-17RE。IL-17C通过IL-17RE和IL-17RA（该家族共享受体）发挥作用，而IL-17A（简称IL-17）通过IL-17RC（特异性受体）和IL-17RA受体二聚体发挥作用。IL-17A在多种炎症性疾病特别是肠道粘膜免疫相关疾病（肠道感染、自身免疫肠炎、肠癌等）的功能研究相对比较清楚。我们之前研究发现IL-17C在肠道感染免疫中发挥了重要的保护作用，与IL-17A的功能类似。但IL-17C在其他炎症性疾病中的功能与机制还不清楚。通过该项目的实施，我们研究发现IL-17C和IL-17A在多种炎症损伤性疾病病理中差别表达调控及功能机制。我们重点研究了IL-17C和IL-17A在自身免疫肠炎及相关肠癌中的差别表达调控机制及功能机制，发现肠道菌群紊乱（特别是肠杆菌）在肠道上皮细胞中通过TLR/MyD88通路诱导IL-17C的表达而IL-17A的诱导表达来源于紊乱菌群诱导的Th17细胞，发现IL-17C和IL-17A分别通过促进肠道上皮细胞的存活和增殖来促进肠道上皮层的损伤修复从而避免了紊乱的菌群引起的自身免疫肠炎，但IL-17C和IL-17A通过促进肠道上皮肿瘤细胞的存活和增殖从而促进了肠炎相关肠癌的发生发展。该项目的研究成果为相关炎症性疾病的治疗提供了的理论基础、潜在新靶标与策略。