甘露聚糖结合凝集素对几种Toll样受体识别配体及其效应的调节作用

Innate immune recognition relies on a limited numbers of pattern recognition receptor (PRR) respond to pathogen-associated molecular pattern (PAMP). Toll like receptor (TLR) and mannan-binding lectin (MBL), two major PRRs, play crucial role in the induction of innate immune response. Our group have recently reported that MBL could regulate the activation of LPS-TLR4 pathway then inhibited the immune fuction of dendritic cell (DC). In addition, we found that MBL could directly interact with TLR4 and the carbohydrate recognition domain (CRD) of MBL bound to TLR ligands specifically. Here, we will extend our study to the relation of MBL and TLRs. First, we will determine the binding characteristics of MBL to TLRs. Secondly, the immunoregulatory role of MBL in TLR pathway will be studied, including the cytokine production by DCs and the antigen presenting capacity of DCs upon TLR ligands stimulation. Furthermore, the regualtion of MBL on TLR mediated immune response and inflammation will be studied. This research will enable us to have a better understanding of the mechanism for innate immune recognition and MBL regulate the TLR mediated innate immune responses and inflammation. The results will provide a theoretical basis for the therapies of infectious diseases.

天然免疫识别由识别病原相关分子模式(PAMP)的模式识别受体(PRR)介导。甘露聚糖结合凝集素（MBL）和Toll样受体 (TLR) 均是参与天然免疫识别的重要PRR。本课题组的最新研究发现MBL参与调节LPS-TLR4通路从而抑制树突状细胞的免疫功能、MBL可与TLR4直接结合且MBL的糖识别域（CRD）可识别TLR配体。据此提出本项目，拟就MBL与TLR之间的相互作用进行下述研究：①MBL与TLR及TLR配体的结合特性；②MBL对TLR信号转导通路的调节；③MBL对TLR配体诱导免疫应答及炎症反应的调节作用。其创新点和意义为：①揭示MBL与TLR及TLR配体的相互作用及其特性，将加深了解天然免疫识别的机理；②阐明MBL对TLR通路调节作用的机制，提出MBL调控TLR介导免疫应答和炎症反应的新观点，将为人工调控有关炎症性疾病提供新的理论依据。

天然免疫识别由识别病原相关分子模式(PAMP)的模式识别受体(PRR)介导。鉴于甘露聚糖结合凝集素（MBL）和Toll样受体 (TLR) 均是参与天然免疫识别的重要PRR在天然免疫识别中的重要作用，阐明MBL与TLR之间的相互关联及MBL对TLR信号通路的调节作用及其机制的重要性不言而喻。本项目就MBL与TLR 之间的相互作用进行了下述研究：①MBL与TLR及TLR配体的结合特性；②MBL 对TLR信号转导通路的调节；③MBL对TLR配体诱导免疫应答及炎症反应的调节作用。现已获得如下结果： ①MBL对poly(I:C)诱导的TLR3信号通路活化的抑制性作用，结果表明MBL可与poly(I:C)及TLR3直接作用从而负向调控相应通路的活化及炎性细胞因子的表达，且CR1和phagosome参与这一调节。此部分结果已发表于FEBS Letter杂志。②MBL负向调节B型CpG-ODN诱导TLR9分泌炎性细胞因子。结果表明MBL可以CpG-ODN结合形成复合物，下调CpG-ODN诱导单核细胞表达炎性细胞因子并抑制其诱导NF-κB p65信号分子的磷酸化。此部分结果已发表于Microbiology and Immunology杂志。此外，在本项目基金的资助下，我们探索了另一重要PRR，清道夫受体A（SRA），在抗病毒免疫防御中的作用，研究结果已发表于BMC Immunology杂志。总之，本项目的主要意义在于：①阐明MBL对TLR3和TLR9识别配体及其效应的调节作用及其分子机制，丰富了天然免疫识别的基础理论。② 揭示MBL对TLR3和TLR9信号活化诱发炎症反应的调节作用。目前，我们已购买MBL缺陷小鼠，将从整体水平研究探讨MBL对天然免疫识别及功能调节这一全新的角度阐述有关免疫相关疾病的发病机理。