Phagocytic Pathway in Macrophages and Dendritic Cells

巨噬细胞具有两大生理功能——宿主防御和清除凋亡细胞及后生动物生理的其他副产物。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后果有很大不同。微生物的吞噬伴随着炎症反应，而凋亡细胞和其他自身物质的吞噬则不伴随炎症反应。这种差异是由于前者中toll样受体（TLRs）的参与，而后者中则不是。我们研究了TLR信号在吞噬过程中的作用。我们的初步数据表明，TLR信号触发了吞噬吞噬率的提高和吞噬酶体融合的诱导模式。我们发现，只有含有TLRs配体的吞噬体才能以诱导速率与溶酶体融合，这表明信号通路存在空间组织机制，负责诱导融合。我们进一步将该途径定义为p38 MAP激酶途径。我们的结果表明，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。本研究的目标是：1)研究TLR的细胞定位和TLR靶向特定区室的机制；2)调查

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.