VEGFR-3调控巨噬细胞TLR4-NF-κB信号通路及保护内毒素性休克的分子机制研究

Sepsis (or septic shock) is the systemic inflammatory response to infection and has a high rate of mortality.Excessive inflammatory responses initiated by TLR4 may disrupt immune homeostasis and result in septic shock.Past efforts have identified multiple intracellular regulators to inhibit TLR4-NF-κB signaling and reduce mortality in response to endotoxin shock. Vascular endothelial growth receptor-3 (VEGFR-3) is the specific receptor of Vascular endothelial growth factor-C and -D (VEGF-C and -D). VEGFR-3 plays a key role in the lymphangiogenesis process. However, little is known about the role and mechanistic basis of VEGFR-3 and its ligands VEGF-C/D on the function of macrophages. Here，we show that VEGFR-3 and VEGF-C are upregulated in LPS or Salmonella typhimurium stimulated macrophages. With VEGFR-3 kinase activity mutant mice, VEGFR-3 ligand-binding activity specifically mutant in macrophages mice and the related stable macrophage cell lines, we will further investigate whether and by which manner VEGFR-3 is involved in TLR4-NF-κB signaling, inflammation responses, and sepsis. The prospective results of this project will not only help to explore the role and mechanistic basis of VEGFR-3 and its ligands VEGF-C/D to regulate TLR4 signaling and systemic sepsis, but also to provide insights on novel therapeutic strategies against infectious or inflammatory diseases.

由细菌感染所导致的败血症是临床上常见的急危重症，死亡率高。其中，TLR4-NF-κB信号转导通路的过度活化与其密切相关。探寻负性调控TLR4-NF-κB信号转导通路的信号分子是近年的研究热点。本项目前期通过筛选细菌感染的巨噬细胞及败血症病人血清，发现血管内皮生长因子受体-3（VEGFR-3）和配体VEGF-C的表达显著上调。前期的工作证明VEGFR-3参与了淋巴管生成，但对VEGFR-3在巨噬细胞介导的炎症及败血症的研究仍是空白。本项目拟借助VEGFR-3胞内区激酶活性位点突变小鼠、胞外配体结合区域缺失的基因工程小鼠，以及相关巨噬细胞稳转株，明确VEGFR-3调节巨噬细胞TLR4-NF-κB信号通路及在炎症和内毒素休克中的保护机制。期望发现新的败血症诊断标志物和药物治疗方案，为发展具有自主知识产权的创新药物和诊断试剂奠定理论和实验基础。

由细菌感染所导致的败血症是临床上常见的急危重症，死亡率高。其中，TLR4-NF-κB信号转导通路的过度活化与其密切相关。探寻负性调控TLR4-NF-κB信号转导通路的信号分子是近年的研究热点。本项目前期通过筛选细菌感染的巨噬细胞及败血症病人血清，发现血管内皮生长因子受体-3（VEGFR-3）和配体VEGF-C的表达显著上调。前期的工作证明VEGFR-3参与了淋巴管生成，但对VEGFR-3在巨噬细胞介导的炎症及败血症的研究仍是空白。本项目拟借助VEGFR-3胞内区激酶活性位点突变小鼠、胞外配体结合区域缺失的基因工程小鼠，以及相关巨噬细胞稳转株，明确VEGFR-3调节巨噬细胞TLR4-NF-κB信号通路及在炎症和内毒素休克中的保护机制。期望发现新的败血症诊断标志物和药物治疗方案，为发展具有自主知识产权的创新药物和诊断试剂奠定理论和实验基础。