Phagocytosis-induced apoptosis in macrophages is mediated by up-regulation and activation of the Bcl-2 homology domain 3-only protein Bim.
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.
Kirschnek
Susanne
S
Institute for Medical Microbiology, Immunology and Hygiene, Technical University Munich, Munich, Germany.
Ying
Songmin
S
Fischer
Silke F
SF
Häcker
Hans
H
Villunger
Andreas
A
Hochrein
Hubertus
H
Häcker
Georg
G
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
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