title: Phagocytosis-induced apoptosis in macrophages is mediated by up-regulation and activation of the Bcl-2 homology domain 3-only protein Bim.
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.
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, Technical University Munich, Munich, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Kirschnek
authors.forename: Songmin
authors.initials: S
authors.lastname: Ying
authors.forename: Silke F
authors.initials: SF
authors.lastname: Fischer
authors.forename: Hans
authors.initials: H
authors.lastname: Häcker
authors.forename: Andreas
authors.initials: A
authors.lastname: Villunger
authors.forename: Hubertus
authors.initials: H
authors.lastname: Hochrein
authors.forename: Georg
authors.initials: G
authors.lastname: Häcker
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000502:physiology; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; D000072224:Bcl-2-Like Protein 11; D002352:Carrier Proteins / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D006098:Granulocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D008562:Membrane Glycoproteins / Q000502:physiology; D008565:Membrane Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053594:Myeloid Differentiation Factor 88; D010587:Phagocytosis / Q000235:genetics / Q000276:immunology*; D010766:Phosphorylation; D020033:Protein Isoforms / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000502:physiology; D011971:Receptors, Immunologic / Q000502:physiology; D040681:Structural Homology, Protein; D051193:Toll-Like Receptors; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C494815:Bid protein, mouse; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D051193:Toll-Like Receptors; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases