Abstract
Cell death by apoptosis is important in immune cell homeostasis and in the defense against infectious microorganisms. The physiological event of uptake and intracellular destruction of bacteria is a powerful apoptotic stimulus to macrophages and neutrophil granulocytes. In this study, we provide a molecular analysis of phagocytosis-induced apoptosis. Apoptosis was blocked by Bcl-2 in a mouse macrophage cell line and in primary mouse macrophages. Analysis of the upstream mechanisms revealed that apoptosis was triggered by the Bcl-2 homology domain 3-only protein Bim/Bod. Contact with bacteria or bacterial components induced a strong increase in Bim-expression through TLR and MyD88. Inhibition of the MAPK p38 and JNK reduced both up-regulation of Bim and apoptosis. Phosphorylation of Bim was further observed in mouse macrophages, which appeared to be the result of TLR-dependent phosphatase inhibition. Although TLR-induced Bim was, unlike Bim in resting cells, not bound to the microtubuli cytoskeleton, the up-regulation of Bim was not sufficient to cause apoptosis. A second signal was required that was generated in the process of phagocytosis. Phagocytosis-induced apoptosis was strongly reduced in Bim(-/-) macrophages. These data provide the molecular context of a form of apoptosis that may serve to dispose of terminally differentiated phagocytes.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Antigens, Differentiation / physiology
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Apoptosis / genetics
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Apoptosis / immunology*
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Apoptosis Regulatory Proteins
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BH3 Interacting Domain Death Agonist Protein
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Bcl-2-Like Protein 11
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Carrier Proteins / biosynthesis
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Carrier Proteins / metabolism
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Carrier Proteins / physiology*
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Cell Line
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Granulocytes / cytology
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Granulocytes / immunology
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Granulocytes / metabolism
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JNK Mitogen-Activated Protein Kinases / physiology
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Macrophage Activation / immunology*
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Macrophages / cytology
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Macrophages / immunology
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Macrophages / metabolism*
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Macrophages / microbiology
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Membrane Glycoproteins / physiology
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Membrane Proteins / biosynthesis
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Membrane Proteins / deficiency
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Membrane Proteins / metabolism
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Membrane Proteins / physiology*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Myeloid Differentiation Factor 88
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Phagocytosis / genetics
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Phagocytosis / immunology*
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Phosphorylation
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Protein Isoforms / metabolism
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Proto-Oncogene Proteins / biosynthesis
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Proto-Oncogene Proteins / deficiency
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins / physiology*
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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Receptors, Cell Surface / physiology
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Receptors, Immunologic / physiology
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Structural Homology, Protein
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Toll-Like Receptors
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Up-Regulation / genetics
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Up-Regulation / immunology*
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p38 Mitogen-Activated Protein Kinases / physiology
Substances
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Adaptor Proteins, Signal Transducing
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Antigens, Differentiation
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Apoptosis Regulatory Proteins
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BH3 Interacting Domain Death Agonist Protein
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Bcl-2-Like Protein 11
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Bcl2l11 protein, mouse
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Bid protein, mouse
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Carrier Proteins
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Membrane Glycoproteins
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Membrane Proteins
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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Protein Isoforms
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Receptors, Cell Surface
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Receptors, Immunologic
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Toll-Like Receptors
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JNK Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases