Phagocytosis-Induced Apoptosis in Macrophages Is Mediated by Up-Regulation and Activation of the Bcl-2 Homology Domain 3-Only Protein Bim

• Published in: The Journal of immunology (1950) 2005-01, Vol.174 (2), p.671-679
• Main Authors: Kirschnek, Susanne, Ying, Songmin, Fischer, Silke F, Hacker, Hans, Villunger, Andreas, Hochrein, Hubertus, Hacker, Georg
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; Animals; Antigens, Differentiation - physiology; Apoptosis - genetics; Apoptosis - immunology; Apoptosis Regulatory Proteins; Bcl-2-Like Protein 11; BH3 Interacting Domain Death Agonist Protein; Carrier Proteins - biosynthesis; Carrier Proteins - metabolism; Carrier Proteins - physiology; Cell Line; Granulocytes - cytology; Granulocytes - immunology; Granulocytes - metabolism; JNK Mitogen-Activated Protein Kinases - physiology; Macrophage Activation - immunology; Macrophages - cytology; Macrophages - immunology; Macrophages - metabolism; Macrophages - microbiology; Membrane Glycoproteins - physiology; Membrane Proteins - biosynthesis; Membrane Proteins - deficiency; Membrane Proteins - metabolism; Membrane Proteins - physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Myeloid Differentiation Factor 88; p38 Mitogen-Activated Protein Kinases - physiology; Phagocytosis - genetics; Phagocytosis - immunology; Phosphorylation; Protein Isoforms - metabolism; Proto-Oncogene Proteins - biosynthesis; Proto-Oncogene Proteins - deficiency; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins - physiology; Proto-Oncogene Proteins c-bcl-2 - metabolism; Receptors, Cell Surface - physiology; Receptors, Immunologic - physiology; Structural Homology, Protein; Toll-Like Receptors; Up-Regulation - genetics; Up-Regulation - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.174.2.671

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.