Phagocytic Pathway in Macrophages and Dendritic Cells

巨噬细胞和树突状细胞的吞噬途径

• 批准号: 7486237
• 负责人: Ruslan Medzhitov
• 金额: $ 53.88万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7486237
• 关键词: Antigen Presentation; Antigen Presentation Pathway; Antigen-Presenting Cells; Apoptotic; Bacteria; CD27 Antigens; Cell membrane; Cells; Chimera organism; Classification; Collaborations; Data; Dendritic Cells; Discrimination; Drosophila genus; Excision; Goals; Gram-Positive Bacteria; Host Defense; Inflammatory Response; Laboratories; Ligands; Localized; Lysosomes; MAPK14 gene; Mammalian Cell; Maps; Microspheres; Molecular; Molecular Target; Numbers; Pathway interactions; Phagocytosis; Phagosomes; Physiological; Physiology; Principal Investigator; Process; Rate; Receptor Signaling; Role; Signal Pathway; Signal Transduction; Specificity; Toll-like receptors; Yeasts; human MAPK14 protein; late endosome; macrophage; microbial; microorganism; mitogen-activated protein kinase p38; pathogen; programs; trafficking; uptake

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.

巨噬细胞有两个主要的生理功能--宿主防御和清除凋亡细胞和其他后生动物生理副产物。这两种功能都依赖于吞噬作用，尽管吞噬细胞摄取微生物病原体和凋亡细胞的后果截然不同。吞噬微生物伴随着炎症反应，而吞噬凋亡细胞和其他自身物质则不伴随。这种差异是由于Toll样受体(TLRs)在前者中的参与，而在后一种情况下则不是。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信号触发了吞噬细胞摄取率的增强和吞噬溶酶体融合的诱导模式。我们发现只有含有TLRs配体的吞噬小体才能以诱导的速度与溶酶体融合，这表明导致融合的信号通路存在空间组织机制。我们进一步将该通路定义为p38 MAP激酶通路。我们的结果：说明含有细菌的吞噬小体的命运与含有凋亡细胞的吞噬小体的命运不同。这项建议的目标是1)研究TLR的细胞定位和负责将TLR差异定位于特定隔区的机制；2)研究 TLR信号在囊泡运输中的作用，特别是在吞噬小体成熟过程中 3)研究TLR诱导的树突状细胞吞噬小体成熟对微生物细胞和凋亡细胞吞噬功能的影响。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在果蝇中观察到的结果进行比较。