Phagocytic Pathway in Macrophages and Dendritic Cells

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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.