Phagocytic Pathway in Macrophages and Dendritic Cells

大型动物有两个主要的生理功能-宿主防御和清除凋亡细胞和后生动物生理学的其他副产物。这两种功能都依赖于吞噬作用，尽管微生物病原体和凋亡细胞的吞噬摄取的结果显著不同。微生物的吞噬作用伴随着炎症反应，而凋亡细胞和其他自身物质的吞噬作用则不伴随。这种差异是由于Toll样受体（TLR）在前者中的参与，而不是在后者的情况。我们研究了TLR信号对吞噬过程的影响。我们的初步数据表明，TLR信号触发增强的吞噬摄取率和吞噬溶酶体融合的诱导模式。我们发现，只有含有TLR配体的吞噬体以诱导的速率与溶酶体融合，这表明存在一种负责可诱导融合的信号通路的空间组织机制。我们进一步将该通路定义为p38 MAP激酶通路。我们的研究结果表明，含有细菌的吞噬体的命运不同于含有凋亡细胞的吞噬体的命运。该提议的目标是1）研究TLR的细胞定位和负责差异TLR靶向特定隔室的机制; 2）研究TLR的细胞定位和靶向特定隔室的机制。 TLR信号在囊泡运输中的作用，特别是在 3）研究TLR诱导的树突状细胞中吞噬体成熟在吞噬微生物细胞和凋亡细胞时的免疫学后果。我们计划与Ezekowitz实验室项目1合作，将哺乳动物细胞中的结果与果蝇中观察到的结果进行比较。

Macrophages have two major physiological functions - host defense and removal of apoptotic cells and other by-products of metazoan physiology. Both of these functions rely on phagocytosis, although the consequences of phagocytic uptake of microbial pathogens and apoptotic cells differ dramatically. Phagocytosis of microorganisms is accompanied by the inflammatory responses, whereas phagocytosis of apoptotic cells and other self material is not. This difference is due to the engagement of Toll-like receptors (TLRs) in the former, but not in the latter case. We investigated the effect of TLR signaling on phagocytic process. Our preliminary data demonstrate that TLR signaling triggers enhanced rate of phagocytic uptake and an inducible mode of phagolysosomal fusion. We found that only the phagosomes that contain TLRs ligands fuse with lysosomes at an induced rate, suggesting the existence of a mechanism of spatial organization of the signaling pathway responsible for the nducible fusion. We further defined the pathway as p38 MAP kinase pathway. Our results :lemonstrate that the fate of phagosomes containing bacteria differs from the fate of phagosomes containing apoptotic cells. The goal of this proposal is 1) to investigate the cellular localization of TLRs and mechanism responsible for differential TLR targeting to specific compartments; 2) to investigate the role of TLR signaling on vesicular trafficking, specifically, in the phagosome maturation in macrophages and dendritic cells upon phagocytosis of microbial and apoptotic cells; 3) to investigate the immunological consequences of TLR-induced phagosome maturation in dendritic cells upon phagocytosis of microbial cells and apoptotic cells. We plan to compare the results in mammalian cells to those observed in Drosophila in collaboration with the Ezekowitz Laboratory, Project 1.