E-selectin调控巨噬细胞IFNγ受体β亚基膜转位参与天然免疫应答的研究

Production of IFNγ is essential to activate macrophage to phagocyte and eliminate intracellular pathogen, and the binding between IFNγ and its receptor is the first step to transfer this signaling pathway, IFNγ receptor is composed of two subunits IFGR1(α) and IFNGR2(β), IFNGR2 on membrane of immunity cells including macrophage is up-regulated during innate immune process, which forms the functional receptors with IFGR1. We occasionally found that the concentration of IFNγ in serum is significantly higher in E-selectin-/- mouse, and while the clearance efficiency of Listeria monocytogenes was inhibited when E-selectin was knock out, further study showed that the expression of IFNγ receptor β on membrane of macrophage is significantly decrease in E-selectin-/- mouse compared with control. Our data further showed that phosphorylation of Syk and Btk is inhibited in macrophage of E-selectin knock-out mouse, and treatment of primary macrophage and cell line RAW with Syk specific inhibitor BAY61-3606 decreased the membrane expression of IFNγ receptor β after activating by LPS. There are no reports about regulation mechanisms of E-selcetin in the process of innate immunity. This project will be focused on the process, which E-selectin mediate the leucocytes rolling on endothelial cell of vessels, initiate the specific signaling pathway and regulate the IFNGR2 expression on membrane of macrophage by modification of this subunit. This study will raise the novel point about the control of IFNGR2 and shed new light on the adherent molecules involving regulation of the function of innate immune cells.

II型干扰素（IFNγ）在抗御胞内菌天然免疫中发挥关键作用，其受体β亚基为可调控亚基，在免疫反应中β亚基在细胞膜表达上调，目前IFNγ受体β亚基（IFNGR2）表达上调的分子机制尚不清楚。我们前期工作偶然发现李斯特菌感染后的E-selectin基因敲除小鼠血清IFNγ浓度显著升高，但细菌清除能力下降，进而发现IFNGR2在E-selectin基因缺陷小鼠的巨噬细胞膜表达明显下调。并发现蛋白激酶Syk和Btk参与了E-selectin对于IFNGR2的调控。针对目前E-selectin调控天然免疫的作用于机制尚未见报道，该申请课题拟阐明在天然免疫反应过程中， E-selectin介导炎性细胞在血管内皮细胞上的机械滚动过程触发胞内信号通路并通过对IFNGR2蛋白修饰，调控β亚基在巨噬细胞膜表达，该课题将对IFNGR2调控机制提出新认识，并对于细胞粘附分子参与天然免疫细胞功能调控研究提出新思路。