VEGFR-3协调调控巨噬细胞自噬胞内细菌和炎症小体活化的新机制研究

Inflammasome and autophagy are essential elements of the innate immune system, and their disruption has been implicated in septic infections and diseases. Our study has identified that the expression of vascular endothelial growth factor C (VEGF-C) and its receptor VEGFR-3, was upregulated on macrophages upon bacterial infection. Upon binding to VEGF-C, VEGFR-3 restrains acute inflammatory responses mediated by macrophage and protects from bacterial infection-triggered sepsis. However, little is known about the role and mechanistic basis of VEGFR-3 and its ligand to regulate autophagy and inflammasome activation. We showed that deficiency of VEGVR-3 signaling promotes internalized TLR4-mediated S. Typhimurium-induced IL-1β production and caspase-1 activation. We will use mice harbor kinase dead or ligand-binding domian deletion in VEGRR-3 to further investigate whether and how VEGFR-3 is involved in autophagy and inflammasome activation. The prospective results of this project will explore the mechanistic basis of VEGFR-3 as a new surface receptor in the coordination of internalized TLR4 to regulate autophagy and inflammasome activation.

在抗感染中，细胞自噬和炎症小体的激活是先天免疫系统应答外界应激的两种至关重要的基本方式。我们前期研究证明细胞表面的血管内皮生长因子受体-3(VEGFR-3)反馈性抑制巨噬细胞TLR4-NF-κB通路诱发的炎症反应，但对VEGFR-3在细菌感染时TLR4介导巨噬细胞异体自噬及炎症小体活化过程中的功能研究仍是空白。本项目前期工作发现VEGFR-3能够促进TLR4介导的吞噬体成熟，同时显著抑制炎症小体的活化并调控IL-1β的分泌。拟借助VEGFR-3胞内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，阐明VEGFR-3参与TLR4相关自噬及炎症小体活化中的调控网络及其在细菌感染中发挥保护作用的分子机制。该研究的创新性在于提出在巨噬细胞控制胞内菌感染时，VEGFR-3作为一种表面受体，辅助TLR4通路调控自噬和炎症小体活化的新型分子机制，将有利于拓展我们对自噬和炎症小体活化的理解。

在抗感染中，细胞自噬和炎症小体的激活是先天免疫系统应答外界应激的两种至关重要的 基本方式。我们前期研究证明细胞表面的血管内皮生长因子受体-3(VEGFR-3)反馈性抑制巨噬 细胞TLR4-NF-κB通路诱发的炎症反应，但对VEGFR-3在细菌感染时TLR4介导巨噬细胞异体自噬 及炎症小体活化过程中的功能研究仍是空白。本项目前期工作发现VEGFR-3能够促进TLR4介导 的吞噬体成熟，同时显著抑制炎症小体的活化并调控IL-1β的分泌。拟借助VEGFR-3胞内激酶 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，阐明VEGFR-3参与TLR4相关自噬 及炎症小体活化中的调控网络及其在细菌感染中发挥保护作用的分子机制。该研究的创新性在 于提出在巨噬细胞控制胞内菌感染时，VEGFR-3作为一种表面受体，辅助TLR4通路调控自噬和 炎症小体活化的新型分子机制，将有利于拓展我们对自噬和炎症小体活化的理解。