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The Role of the Macrophage in Apoptosis: Hunter, Gatherer, and Regulator

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Abstract

Clearance of cellular corpses is a critical feature of apoptosis in vivo during development, tissue homeostasis, and resolution of inflammation. As the professional phagocytes of the body, macrophages play a key role in this process. By recognizing emerging signals using several different receptors, macrophages engulf apoptotic cells swiftly and efficiently. In addition, the binding of apoptotic cells profoundly down-regulates the ability of the macrophage to produce inflammatory mediators by inducing the release of antiinflammatory mediators. Finally, macrophages may actually induce cell death in specific cells during embryogenesis.Abnormalities of apoptotic cell clearance may contribute to the pathogenesis of chronic inflammatory diseases, including those of autoimmune etiology. It is also possible that certain malignant tumor cells co-opt the mechanisms for apoptotic cell clearance to avoid immune surveillance by subverting macrophage and dendritic cell responses.

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References

  1. Fadok VA,Voelker DR, Campbell PA, Cohen JJ, Bratton DL, Henson PM. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages.J Immunol. 1992;148:2207–2216.

    CAS  PubMed  Google Scholar 

  2. Fadok VA, Bratton DL, Frasch SC, Warner ML, Henson PM. The role of phosphatidylserine in recognition of apoptotic cells by phagocytes.Cell Death Differ. 1998;5:551–562.

    Article  CAS  PubMed  Google Scholar 

  3. Tanaka Y, Schroit AJ. Insertion of fluorescent phosphatidylserine into the plasma membrane of red blood cells.J Biol Chem. 1983; 258:11335–11343.

    CAS  PubMed  Google Scholar 

  4. Schroit AJ, Madsen JW, Tanaka Y.In vivo recognition and clearance of red blood cells containing phosphatidylserine in their plasma membranes.J Biol Chem. 1985;260:5131–5138.

    CAS  PubMed  Google Scholar 

  5. Schwartz RS, Tanaka Y, Fidler IJ, Chiu DT, Lubin B, Schroit AJ. Increased adherence of sickled and phosphatidylserine-enriched human erythrocytes to cultured human peripheral blood monocytes.J Clin Invest. 1985;75:1965–1972.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Savill J, Fadok V. Corpse clearance defines the meaning of cell death.Nature. 2000;407:784–788.

    Article  CAS  PubMed  Google Scholar 

  7. Fadok VA, Bratton DL, Henson PM. Phagocyte receptors for apoptotic cells: recognition, uptake, and consequences.J Clin Invest. 2001;108:957–962.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Henson PM, Bratton DL, Fadok VA. Apoptotic cell removal.Curr Biol. 2001;11:R795-R805.

    Article  CAS  PubMed  Google Scholar 

  9. Hamon Y, Broccardo C, Chambenoit O, et al. ABC1 promotes engulfment of apoptotic cells and transbilayer redistribution of phosphatidylserine.Nat Cell Biol. 2000;2:399–406.

    Article  CAS  PubMed  Google Scholar 

  10. Fadeel B, Gleiss B, Hogstrand K, et al. Phosphatidylserine exposure during apoptosis is a cell-type-specific event and does not correlate with plasma membrane phospholipid scramblase expression.Biochem Biophys Res Commun. 1999;266:504–511.

    Article  CAS  PubMed  Google Scholar 

  11. Fadok VA, deCathelineau A, Daleke DL, Henson PM, Bratton DL. Loss of phospholipid asymmetry and surface exposure of phosphatidylserine is required for phagocytosis of apoptotic cells by macrophages and fibroblasts.J Biol Chem. 2001;276: 1071–1077.

    Article  CAS  PubMed  Google Scholar 

  12. Duvall E, Wyllie AH, Morris RG. Macrophage recognition of cells undergoing programmed cell death (apoptosis).Immunology. 1985;56:351–358.

    PubMed Central  CAS  PubMed  Google Scholar 

  13. Beppu M. Mechanism of removal of aged cells, oxidized cells and apoptotic cells through carbohydrate chains.Seikagaku. 2001;73: 196–200.

    CAS  PubMed  Google Scholar 

  14. Ruzittu M, Carla EC, Montinari MR, Maietta G, Dini L. Modulation of cell surface expression of liver carbohydrate receptors during in vivo induction of apoptosis with lead nitrate.Cell Tissue Res. 1999;298:105–112.

    Article  CAS  PubMed  Google Scholar 

  15. Dini L, Carla EC. Hepatic sinusoidal endothelium heterogeneity with respect to the recognition of apoptotic cells.Exp Cell Res. 1998;240:388–393.

    Article  CAS  PubMed  Google Scholar 

  16. Falasca L, Bergamini A, Serafino A, Balabaud C, Dini L. Human Kupffer cell recognition and phagocytosis of apoptotic peripheral blood lymphocytes.Exp Cell Res. 1996;224:152–162.

    Article  CAS  PubMed  Google Scholar 

  17. Dini L, Autuori F, Lentini A, Oliverio S, Piacentini M. The clearance of apoptotic cells in the liver is mediated by the asialoglyco-protein receptor.FEBS Lett. 1992;296:174–178.

    Article  CAS  PubMed  Google Scholar 

  18. Moffatt OD, Devitt A, Bell ED, Simmons DL, Gregory CD. Macrophage recognition of ICAM-3 on apoptotic leukocytes.J Immunol. 1999;162:6800–6810.

    CAS  PubMed  Google Scholar 

  19. Devitt A, Moffatt OD, Raykundalia C, Capra JD, Simmons DL, Gregory CD. Human CD14 mediates recognition and phagocytosis of apoptotic cells.Nature. 1998;392:505–509.

    Article  CAS  PubMed  Google Scholar 

  20. Gregory CD. CD14-dependent clearance of apoptotic cells: relevance to the immune system.Curr Opin Immunol. 2000;12:27–34.

    Article  CAS  PubMed  Google Scholar 

  21. Oka K, Sawamura T, Kikuta K-I, et al. Lectin-like oxidized low-density lipoprotein receptor 1 mediates phagocytosis of aged/apoptotic cells in endothelial cells.Proc Natl Acad Sci U S A. 1998;95: 9535–340.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Ramprasad MP, Fischer W, Witztum JL, Sambrano GR, Quehen-berger O, Steinberg D. The 94- to 97-kDa mouse macrophage membrane protein that recognizes oxidized low density lipoprotein and phosphatidylserine-rich liposomes is identical to macrosialin, the mouse homologue of human CD68.Proc Natl Acad Sci U S A. 1995;92:9580–9584.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Sambrano GR, Steinberg D. Recognition of oxidatively damaged and apoptotic cells by an oxidized low density lipoprotein receptor on mouse peritoneal macrophages: role of membrane phos-phatidylserine.Proc Natl Acad Sci U S A. 1995;92:1396–1400.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Terpstra V, Bird DA, Steinberg D. Evidence that the lipid moiety of oxidized low density lipoprotein plays a role in its interaction with macrophage receptors.Proc Natl Acad Sci U S A. 1998;95: 1806–1811.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Chang M-K, Bergmark C, Laurila A, et al. Monoclonal antibodies against oxidized low-density lipoprotein bind to apoptotic cells and inhibit their phagocytosis by elicited macrophages: evidence that oxidation-specific epitopes mediate macrophage recognition.Proc Natl Acad Sci U S A. 1999;96:6353–6358.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Kagan VE, Fabisiak JP, Shvedova AA, et al. Oxidative signaling pathway for externalization of plasma membrane phosphatidylserine during apoptosis.FEBS Lett. 2000;477:1–7.

    Article  CAS  PubMed  Google Scholar 

  27. Tyurina YY, Shvedova AA, Kawai K, et al. Phospholipid signaling in apoptosis: peroxidation and externalization of phosphatidylserine.Toxicology. 2000;148:93–101.

    Article  CAS  PubMed  Google Scholar 

  28. Schor NF, Tyurina YY, Fabisiak JP, Tyurin VA, Lazo JS, Kagan VE. Selective oxidation and externalization of membrane phos-phatidylserine: Bcl-2-induced potentiation of the final common pathway for apoptosis.Brain Res. 1999;831:125–130.

    Article  CAS  PubMed  Google Scholar 

  29. Fabisiak JP, Tyurina YY, Tyurin VA, Lazo JS, Kagan VE. Random versus selective membrane phospholipid oxidation in apoptosis: role of phosphatidylserine.Biochemistry. 1998;37:13781–13790.

    Article  CAS  PubMed  Google Scholar 

  30. Fabisiak JP, Kagan VE, Ritov VB, Johnson DE, Lazo JS. Bcl-2 inhibits selective oxidation and externalization of phosphatidylserine during paraquat-induced apoptosis.Am J Physiol. 1997; 272:C675-C684.

    Article  CAS  PubMed  Google Scholar 

  31. Fujii C, Shiratsuchi A, Manaka J, Yonehara S, Nakanishi Y. Difference in the way of macrophage recognition of target cells depending on their apoptotic states.Cell Death Differ. 2001;8:1113–1122.

    Article  CAS  PubMed  Google Scholar 

  32. Balasubramanian K, Chandra J, Schroit AJ. Immune clearance of phosphatidylserine-expressing cells by phagocytes: the role of β2-glycoprotein 1 in macrophage recognition.J Biol Chem. 1997;272: 31113–31117.

    Article  CAS  PubMed  Google Scholar 

  33. Chonn A, Semple SC, Cullis PR. β2-glycoprotein 1 is a major protein associated with very rapidly cleared liposomesin vivo, suggesting a significant role in the immune clearance of “non-self” particles.J Biol Chem. 1995;270:25845–25849.

    Article  CAS  PubMed  Google Scholar 

  34. Nakano T, Ishimoto Y, Kishino J, et al. Cell adhesion to phosphatidylserine mediated by a product of growth arrest-specific gene 6.J Biol Chem. 1997;272:29411–29414.

    Article  CAS  PubMed  Google Scholar 

  35. Korb LC, Ahearn JM. C1q binds directly and specifically to surface blebs of apoptotic human keratinocytes: complement deficiency and systemic lupus erythematosus revisited.J Immunol. 1997;158: 4525–4528.

    CAS  PubMed  Google Scholar 

  36. Taylor PR, Carugati A, Fadok VA, et al. A hierarchical role for classical pathway complement proteins in the clearance of apoptotic cells in vivo.J Exp Med. 2000;192:359–366.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Ogden CA, deCathelineau A, Hoffman PR, et al. C1q and mannose binding lectin engagement of cell surface calreticulin and CD91 initiates macropinocytosis and uptake of apoptotic cells.J Exp Med. 2001;194:781–795.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Gershov D, Kim S, Brot N, Elkon KB. C-reactive protein binds to apoptotic cells, protects the cells from assembly of the terminal complement components, and sustains an antiinflammatory innate immune response: implications for systemic autoimmunity.J Exp Med. 2000;192:1353–1363.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Mevorach D, Mascarenhas JO, Gershov D, Elkon KB. Complement-dependent clearance of apoptotic cells by human macrophages.J Exp Med. 1998;188:2313–2320.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Rovere P, Peri G, Fazzini F, et al. The long pentraxin PTX3 binds to apoptotic cells and regulates their clearance by antigen-presenting dendritic cells.Blood. 2000;96:4300–4306.

    CAS  PubMed  Google Scholar 

  41. Savill J, Hogg N, Ren Y, Haslett C. Thrombospondin cooperates with CD36 and the vitronectin receptor in macrophage recognition of neutrophils undergoing apoptosis.J Clin Invest. 1992;90: 1513–1522.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Fadok VA, Warner ML, Bratton DL, Henson PM. CD36 is required for phagocytosis of apoptotic cells by human macrophages that use either a phosphatidylserine receptor or the vitronectin receptor (αVβ3).J Immunol. 1998;161:6250–6257.

    CAS  PubMed  Google Scholar 

  43. Schagat TL, Wofford JA, Wright JR. Surfactant protein A enhances alveolar macrophage phagocytosis of apoptotic neutrophils.J Immunol. 2001;166:2727–2733.

    Article  CAS  PubMed  Google Scholar 

  44. Wiegand UK, Corbach S, Prescott AR, Savill J, Spruce BA. The trigger to cell death determines the efficiency with which dying cells are cleared by neighbors.Cell Death Differ. 2001;8:734–746.

    Article  CAS  PubMed  Google Scholar 

  45. Luciani M-F, Chimini G. The ATP binding cassette transporter ABC1, is required for the engulfment of corpses generated by apoptotic cell death. EMBO J. 1996;15:226–235.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Callahan MK, Williamson P, Schlegel RA. Surface expression of phosphatidylserine on macrophages is required for phagocytosis of apoptotic thymocytes.Cell Death Differ. 2000;7:645–653.

    Article  CAS  PubMed  Google Scholar 

  47. Ramprasad MP, Terpstra V, Kondratenko N, Quehenberger O, Steinberg D. Cell surface expression of mouse macrosialin and human CD68 and their role as macrophage receptors for oxidized low density lipoprotein.Proc Natl Acad Sci U S A. 1996;93: 14833–14838.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Ottnad E, Parthasarathy S, Sambrano GR, et al. A macrophage receptor for oxidized low density lipoprotein distinct from the receptor for acetyl low density lipoprotein: partial purification and role in recognition of oxidatively damaged cells.Proc Natl Acad Sci U S A. 1995;92:1391–1395.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Endemann G, Stanton LW, Madden KS, Bryant CM, White RT, Protter AA. CD36 is a receptor for oxidized low density lipoprotein.J Biol Chem. 1993;268:11811–11816.

    CAS  PubMed  Google Scholar 

  50. Stern M, Savill J, Haslett C. Human monocyte-derived macrophage phagocytosis of senescent eosinophils undergoing apoptosis: mediation by αvβ3/CD36/thrombospondin recognition mechanism and lack of phlogistic response.Am J Pathol. 1996;149:911–921.

    PubMed Central  CAS  PubMed  Google Scholar 

  51. Ren Y, Silverstein RL, Allen J, Savill J. CD36 gene transfer confers capacity for phagocytosis of cells undergoing apoptosis.J Exp Med. 1995;181:1857–1862.

    Article  CAS  PubMed  Google Scholar 

  52. Tait JF, Smith C. Phosphatidylserine receptors: role of CD36 in binding of anionic phospholipid vesicles to monocytic cells.J Biol Chem. 1999;274:3048–3054.

    Article  CAS  PubMed  Google Scholar 

  53. Savill J, Dransfield I, Hogg N, Haslett C. Vitronectin receptor-mediated phagocytosis of cells undergoing apoptosis.Nature. 1990;343: 170–173.

    Article  CAS  PubMed  Google Scholar 

  54. Rigotti A, Acton SL, Krieger M. The class B scavenger receptors SR-B1 and CD36 are receptors for anionic phospholipids.J Biol Chem. 1995;270:16221–16224.

    Article  CAS  PubMed  Google Scholar 

  55. Fukasawa M, Adachi H, Hirota K,Tsujimoto M, Arai H, Inoue K. SRB1, a class B scavenger receptor, recognizes both negatively charged liposomes and apoptotic cells.Exp Cell Res. 1996;222: 246–250.

    Article  CAS  PubMed  Google Scholar 

  56. Murao K,Terpstra V, Green SR, Kondratenko N, Steinberg D, Quehenberger O. Characterization of CLA-1, a human homologue of rodent scavenger receptor BI, as a receptor for high density lipoprotein and apoptotic thymocytes.J Biol Chem. 1997;272: 17551–17557.

    Article  CAS  PubMed  Google Scholar 

  57. Graham DK, Bowman GW, Dawson TL, Stanford WL, Earp HS, Snodgrass HR. Cloning and developmental expression analysis of the murinec-mer tyrosine kinase.Oncogene. 1995;10:2349–2359.

    CAS  PubMed  Google Scholar 

  58. Camenisch TD, Koller BH, Earp HS, Matsushima GK. A novel receptor tyrosine kinase, mer, inhibits TNF-α production and lipopolysaccharide-induced endotoxic shock.J Immunol. 1999;162: 3498–3503.

    CAS  PubMed  Google Scholar 

  59. Nagata K, Ohashi K, Nakano T, et al. Identification of the product of growth arrest-specific gene6 as a common ligand for axl, sky, and mer receptor tyrosine kinases.J Biol Chem. 1996;271: 30022–30027.

    Article  CAS  PubMed  Google Scholar 

  60. Ishimoto Y, Ohashi K, Mizuno K, Nakano T. Promotion of the uptake of PS liposomes and apoptotic cells by a product of growth arrest-specific gene, gas6.J Biochem (Tokyo). 2000;127:411–417.

    Article  CAS  Google Scholar 

  61. Scott RS, McMahon EJ, Pop SM, et al. Phagocytosis and clearance of apoptotic cells is mediated by MER.Nature. 2001;411:207–211.

    Article  CAS  PubMed  Google Scholar 

  62. Navratil JS, Watkins SC, Wisnieski JJ, Ahearn JM. The globular heads of C1q specifically recognize surface blebs of apoptotic vascular endothelial cells.J Immunol. 2001;166:3231–3239.

    Article  CAS  PubMed  Google Scholar 

  63. Botto M, Dell’Agnola C, Bygrave AE, et al. Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies.Nat Genet. 1998;19:56–59.

    Article  CAS  PubMed  Google Scholar 

  64. Herz J, Strickland DK. LRP: a multifunctional scavenger and signaling receptor.J Clin Invest. 2001;108:779–784.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. Basu S, Binder RJ, Ramalingam T, Srivastava PK. CD91 is a common receptor for heat shock proteins gp96, hsp90, hsp70, and cal-reticulin.Immunity. 2001;14:303–313.

    Article  CAS  PubMed  Google Scholar 

  66. Fadok VA, Savill JS, Haslett C, et al. Different populations of macrophages use either the vitronectin receptor or the phosphatidylserine receptor to recognize and remove apoptotic cells.J Immunol. 1992;149:4029–4035.

    CAS  PubMed  Google Scholar 

  67. Fadok VA, Bratton DL, Rose DM, Pearson A, Ezekewitz RAB, Henson PM. A receptor for phosphatidylserine-specific clearance of apoptotic cells.Nature. 2000;405:85–90.

    Article  CAS  PubMed  Google Scholar 

  68. Clissold PM, Ponting CP. JmjC: cupin metalloenzyme-like domains in jumonji, hairless and phospholipase A2β.Trends Biochem Sci. 2001;26:7–9.

    Article  CAS  PubMed  Google Scholar 

  69. Kurosaka K, Watanabe N, Kobayashi Y. Production of proinflammatory cytokines by resident tissue macrophages after phagocytosis of apoptotic cells.Cell Immunol. 2001;211:1–7.

    Article  CAS  PubMed  Google Scholar 

  70. Misawa R, Kawagishi C, Watanabe N, Kobayashi Y. Infiltration of neutrophils following injection of apoptotic cells into the peritoneal cavity.Apoptosis. 2001;6:411–417.

    Article  CAS  PubMed  Google Scholar 

  71. Savill J, Fadok V, Henson P, Haslett C. Phagocyte recognition of cells undergoing apoptosis.Immunol Today. 1993;14:131–136.

    Article  CAS  PubMed  Google Scholar 

  72. Meagher LC, Savill JS, Baker A, Fuller RW, Haslett C. Phagocytosis of apoptotic neutrophils does not induce macrophage release of thromboxane B2.J Leukoc Biol. 1992;52:269–273.

    Article  CAS  PubMed  Google Scholar 

  73. Ren Y, Stuart L, Lindberg FP, et al. Nonphlogistic clearance of late apoptotic neutrophils by macrophages: efficient phagocytosis independent of β2 integrins.J Immunol. 2001;166:4743–4750.

    Article  CAS  PubMed  Google Scholar 

  74. Fadok VA, Bratton DL, Guthrie L, Henson PM. Differential effects of apoptotic versus lysed cells on macrophage production of cytokines: role of proteases.J Immunol. 2001;166:6847–6854.

    Article  CAS  PubMed  Google Scholar 

  75. Voll RE, Herrmann M, Roth EA, Stach C, Kalden JR, Girkontaite I. Immunosuppressive effects of apoptotic cells.Nature. 1997;390: 350–351.

    Article  CAS  PubMed  Google Scholar 

  76. Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/ paracrine mechanisms involving TGF-β, PGE2, and PAF.J Clin Invest. 1998;101:890–898.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  77. McDonald PP, Fadok VA, Bratton D, Henson PM. Transcriptional and translational regulation of inflammatory mediator production by endogenous TGF-β in macrophages that have ingested apoptotic cells.J Immunol. 1999;163:6164–6172.

    CAS  PubMed  Google Scholar 

  78. Fadok VA, Xue D, Henson P. If phosphatidylserine is the death knell, a new phosphatidylserine-specific receptor is the bellringer.Cell Death Differ. 2001;8:582–587.

    Article  CAS  PubMed  Google Scholar 

  79. Henson PM, Bratton DL, Fadok VA. The phosphatidylserine receptor: a crucial molecular switch?Nat Rev Mol Cell Biol. 2001; 2:627–633.

    Article  CAS  PubMed  Google Scholar 

  80. Hoffmann PR, deCathelineau AM, Ogden CA, et al. Phosphatidylserine (PS) induces PS receptor-mediated macropinocytosis and promotes clearance of apoptotic cells.J Cell Biol. 2001;155: 649–659.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  81. Huynh M-LN, Fadok VA, Henson PM. Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-β1 secretion and the resolution of inflammation.J Clin Invest. 2001;109:41–50.

    Article  Google Scholar 

  82. Cocco RE, Ucker DS. Distinct modes of macrophage recognition for apoptotic and necrotic cells are not specified exclusively by phosphatidylserine exposure.Mol Biol Cell. 2001;12:919–930.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  83. Vandivier RW, Fadok VA, Hoffmann PR, et al. Elastase-mediated phosphatidylserine receptor cleavage impairs apoptotic cell clearance in cystic fibrosis and bronchiectasis.J Clin Invest. 2002;109: 661–670.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  84. Gumienny TL, Hengartner MO. How the worm removes corpses: the nematodeC. elegans as a model system to study engulfment.Cell Death Differ. 2001;8:564–568.

    Article  CAS  PubMed  Google Scholar 

  85. Ellis RE, Jacobson DM, Horvitz HR. Genes required for the engulfment of cell corpses during programmed cell death inCaenorhabditis elegans.Genetics. 1991;129:79–94.

    PubMed Central  CAS  PubMed  Google Scholar 

  86. Fadok VA, Henson PM. Apoptosis: getting rid of the bodies.Curr Biol. 1998;8:R693-R695.

    Article  CAS  PubMed  Google Scholar 

  87. Hengartner MO. Apoptosis: corralling the corpses.Cell. 2001;104: 325–328.

    Article  CAS  PubMed  Google Scholar 

  88. Zhou Z, Hartwieg E, Horvitz HR. CED-1 is a transmembrane receptor that mediates cell corpse engulfment inC. elegans.Cell. 2001;104:43–56.

    Article  CAS  PubMed  Google Scholar 

  89. Su HP, Nakada-Tsukui K, Tosello-Trampont A-C, et al. Interaction of CED-6/GULP, an adapter protein involved in engagement of apoptotic cells, with CED-1 and CD91/LRP.J Biol Chem. 2002;277: 11772–11779.

    Article  CAS  PubMed  Google Scholar 

  90. Liu QA, Hengartner MO. Human CED-6 encodes a functional homologue of theCaenorhabditis elegans engulfment protein CED-6.Curr Biol. 1999;9:1347–1350.

    Article  CAS  PubMed  Google Scholar 

  91. Smits E, Van Criekinge W, Plaetinck G, Bogaert T. The human homologue ofCaenorhabditis elegans CED-6 specifically promotes phagocytosis of apoptotic cells.Curr Biol. 1999;9:1351–1354.

    Article  CAS  PubMed  Google Scholar 

  92. Su HP, Brugnera E, Criekinge WV, et al. Identification and characterization of a dimerizatioin domain in CED-6, an adapter protein involved in engulfment of apoptotic cells.J Biol Chem. 2000;275: 9542–9549.

    Article  CAS  PubMed  Google Scholar 

  93. Wu Y-C, Horvitz HR. TheC. elegans cell corpse engulfment geneced-7 encodes a protein similar to ABC transporters.Cell. 1998;93: 951–960.

    Article  CAS  PubMed  Google Scholar 

  94. Wu Y-C, Horvitz HR.C. elegans phagocytosis and cell-migration protein CED-5 is similar to human DOCK180.Nature. 1998;392: 501–504.

    Article  CAS  PubMed  Google Scholar 

  95. Reddien PW, Horvitz HR. CED-2/CrkII and CED-10/Rac control phagocytosis and cell migration inCaenorhabditis elegans.Nat Cell Biol. 2000;2:131–136.

    Article  CAS  PubMed  Google Scholar 

  96. Gumienny TL, Brugnera E, Tosello-Trampont A-C, et al. CED-12/ ELMO, a novel member of the CrkII/Dock180/Rac pathway, is required for phagocytosis and cell migration.Cell. 2001;107:27–41.

    Article  CAS  PubMed  Google Scholar 

  97. Albert ML, Kim J-I, Birge RB. αvβ5 integrin recruits the CrkII-Dock180-Rac1 complex for phagocytosis of apoptotic cells.Nat Cell Biol. 2000;2:899–905.

    Article  CAS  PubMed  Google Scholar 

  98. Tosello-Trampont A-C, Brugnera E, Ravichandran KS. Evidence for a conserved role for CrkII and Rac in engulfment of apoptotic cells.J Biol Chem. 2001;276:13797–13802.

    Article  CAS  PubMed  Google Scholar 

  99. Pradhan D, Krahling S, Williamson P, Schlegel RA. Multiple systems for recognition of apoptotic lymphocytes by macrophages.Mol Biol Cell. 1997;8:767–778.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  100. Jacobson MD, Weil M, Raff MC. Programmed cell death in animal development.Cell. 1997;88:347–354.

    Article  CAS  PubMed  Google Scholar 

  101. Vaux DL, Korsmeyer SJ. Cell death in development.Cell. 1999;96:#@#245–254.

    Article  CAS  PubMed  Google Scholar 

  102. Morris L, Graham CF, Gordon S. Macrophages in haemopoietic#@#and other tissues of the developing mouse detected by the monoclonal#@#antibody F4/80.Development. 1991;112:517–526.

    CAS  PubMed  Google Scholar 

  103. Hopkinson-Woolley J, Hughes D, Gordon S, Martin P. Macrophage#@#recruitment during limb development and wound healing in the#@#embryonic and foetal mouse.J Cell Sci. 1994;107:1159–1167.

    PubMed  Google Scholar 

  104. Lang RA, Bishop JM. Macrophages are required for cell death and#@#tissue remodeling in the developing mouse eye.Cell. 1993;74:#@#453–462.

    Article  CAS  PubMed  Google Scholar 

  105. Lang R, Lustig M, Francois F, Sellinger M, Plesken H. Apoptosis#@#during macrophage-dependent ocular tissue remodeling.Development.#@#1994;120:3395–3403.

    CAS  PubMed  Google Scholar 

  106. Hume DA, Perry VH, Gordon S. Immunohistochemical localization#@#of a macrophage-specific antigen in developing mouse retina:#@#phagocytosis of dying neurons and differentiation of microglial#@#cells to form a regular array in the plexiform layers.J Cell Biol.#@#1983;97:253–257.

    Article  CAS  PubMed  Google Scholar 

  107. Camp V, Martin P. The role of macrophages in clearing programmed#@#cell death in the developing kidney.Anat Embryol. 1996;#@#194:341–348.

    Article  CAS  PubMed  Google Scholar 

  108. Perry VH, Hume DA, Gordon S. Immunohistochemical localization#@#of macrophages and microglia in the adult and developing#@#mouse brain.Neuroscience. 1985;15:313–326.

    Article  CAS  PubMed  Google Scholar 

  109. Cuadros MA, Martin C, Coltey P, Almendros A, Navascues J. First#@#appearance, distribution, and origin of macrophages in the early#@#development of the avian central nervous system.J Comp Neurol.#@#1993;330:113–129.

    Article  CAS  PubMed  Google Scholar 

  110. Wood W, Turmaine M, Weber R, et al. Mesenchymal cells engulf#@#and clear apoptotic footplate cells in macrophageless PU.1 null#@#mouse embryos.Development. 2000;127:5245–5522.

    CAS  PubMed  Google Scholar 

  111. Aliprantis AO, Diez-Roux G, Mulder LCF, Zychlinsky A, Lang RA. Do macrophages kill through apoptosis?Immunol Today.#@#1996;17:573–576.

    Article  CAS  PubMed  Google Scholar 

  112. Diez-Roux G, Lang RA. Macrophages induce apoptosis in normal#@#cells in vivo.Development. 1997;124:3633–3638.

    CAS  PubMed  Google Scholar 

  113. Diez-Roux G,Argilla M,Makarenkova H, Ko K, Lang RA. Macrophages#@#kill capillary cells in G1 phase of the cell cycle during programmed#@#vascular regression.Development. 1999;126:2141–2147.

    CAS  PubMed  Google Scholar 

  114. Hensey C, Gautier J. Programmed cell death during Xenopus#@#development: a spatio-temporal analysis.Dev Biol. 1998;203:36–48.

    Article  CAS  PubMed  Google Scholar 

  115. Kerr JF, Harmon B, Searle J. An electron-microscope study of cell#@#deletion in the anuran tadpole tail during spontaneous metamorphosis#@#with special reference to apoptosis of striated muscle fibers.#@#J Cell Sci. 1974;14:571–585.

    CAS  PubMed  Google Scholar 

  116. Ishizuya-Oka A, Shimozawa A. Programmed cell death and het-erolysis#@#of larval epithelial cells by macrophage-like cells in the#@#anuran small intestine in vivo and in vitro.J Morphol. 1992;213:#@#185–195.

    Article  CAS  PubMed  Google Scholar 

  117. Nishikawa A, Murata E, Akita M, et al. Roles of macrophages in#@#programmed cell death and remodeling of tail and body muscle of#@#Xenopus laevis during metamorphosis.Histochem Cell Biol. 1998;#@#109:11–17.

    Article  CAS  PubMed  Google Scholar 

  118. Little GH, Flores A. Inhibition of programmed cell death by cata-lase#@#and phenylalanine methyl esterase.Comp Biochem Physiol#@#Comp Physiol. 1993;105:79–83.

    Article  CAS  Google Scholar 

  119. Gouon-Evans V, Rothenberg ME, Pollard JW. Postnatal mammary#@#gland development requires macrophages and eosinophils.Development.#@#2000;127:2269–2282.

    CAS  PubMed  Google Scholar 

  120. Pollard JW, Hennighausen L. Colony stimulating factor 1 is#@#required for mammary gland development during pregnancy.Proc#@#Natl Acad Sci U S A. 1994;91:9312–9316.

    Article  CAS  Google Scholar 

  121. Kiener PA, Davis PM, Rankin BM, et al. Human monocytic cells#@#contain high levels of intracellular fas ligand.J Immunol. 1997;159:#@#1594–1598.

    CAS  PubMed  Google Scholar 

  122. Kiener PA, Davis PM, Starling GC, et al. Differential induction of#@#apoptosis by fas-fas ligand interactions in human monocytes and#@#macrophages.J Exp Med. 1997;185:1511–1516.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  123. Brown SB, Savill J. Phagocytosis triggers macrophage release of fas#@#ligand and induces apoptosis of bystander leukocytes.J Immunol.#@#1999;162:480–485.

    CAS  PubMed  Google Scholar 

  124. Cui S, Reichner JS, Mateo RB,Albina JE. Activated murine macrophages#@#induce apoptosis in tumor cells through nitric oxide-dependent#@#or -independent mechanisms.Cancer Res. 1994;54:#@#2462–2467.

    CAS  PubMed  Google Scholar 

  125. Hoeppner DJ, Hengartner MO, Schnabel R. Engulfment genes#@#cooperate withced-3 to promote cell death inCaenorhabditis elegans.#@#Nature. 2001;412:202–206.

    Article  CAS  PubMed  Google Scholar 

  126. Reddien PW, Cameron S, Horvitz HR. Phagocytosis promotes programmed#@#cell death inC. elegans.Nature. 2001;412:198–202.

    Article  CAS  PubMed  Google Scholar 

  127. Green DR, Beere HM. Mostly dead.Nature. 2001;412:133–135.

    Article  CAS  PubMed  Google Scholar 

  128. Geske FJ, Lieberman R, Strange R, Gerschenson LE. Early stages#@#of p53-induced apoptosis are reversible.Cell Death Differ. 2001;8:#@#182–191.

    Article  CAS  PubMed  Google Scholar 

  129. Savill J. Apoptosis in disease.Eur J Clin Invest. 1994;24:715–723.

    Article  CAS  PubMed  Google Scholar 

  130. Haslett C, Savill JS, Whyte MKB, Stern M, Dransfield I, Meagher LC. Granulocyte apoptosis and the control of inflammation.Philos#@#Trans R Soc Lond B Biol Sci. 1994;345:327–333.

    Article  CAS  Google Scholar 

  131. Grigg JM, Savill JS, Sarraf C, Haslett C, Silverman M. Neutrophil#@#apoptosis and clearance from neonatal lungs.Lancet. 1991;338:#@#720–722.

    Article  CAS  PubMed  Google Scholar 

  132. Savill JS, Wyllie AH, Henson JE, Walport MJ, Henson PM, Haslett C. Macrophage phagocytosis of aging neutrophils in inflammation:#@#programmed cell death in the neutrophil leads to its recognition by#@#macrophages.J Clin Invest. 1989;83:865–875.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  133. Hughes J, Johnson RJ, Mooney A, Hugo C, Gordon K, Savill J.#@#Neutrophil fate in experimental glomerular capillary injury in the#@#rat.Am J Pathol. 1997;150:223–234.

    PubMed Central  CAS  PubMed  Google Scholar 

  134. Savill J, Smith J, Sarraf C, Ren Y, Abbott F, Rees A. Glomerular mesangial cells and inflammatory macrophages ingest neutrophils#@#undergoing apoptosis.Kidney Int. 1992;42:924–936.

    Article  CAS  PubMed  Google Scholar 

  135. Savill J. Apoptosis: a mechanism for regulation of the cell complement#@#of inflamed glomeruli.Kidney Int. 1992;41:607–612.

    Article  CAS  PubMed  Google Scholar 

  136. Morimoto K, Amano H, Sonoda F, et al. Alveolar macrophages#@#that phagocytose apoptotic neutrophils produce hepatocyte#@#growth factor during bacterial pneumonia in mice.Am J Respir#@#Cell Mol Biol. 2001;24:608–615.

    Article  CAS  Google Scholar 

  137. Holmgren L, Szeles A, Rajnavolgyi E, et al. Horizontal transfer of#@#DNA by the uptake of apoptotic bodies.Blood. 1999;93:3956–3963.

    CAS  PubMed  Google Scholar 

  138. Spetz A-L, Patterson BK, Lore K,Andersson J, Holmgren L. Functional#@#gene transfer of HIV DNA by an HIV receptor-independent#@#mechanism.J Immunol. 1999;163:736–742.

    CAS  PubMed  Google Scholar 

  139. Bergsmedh A, Szeles A, Henriksson M, et al. Horizontal transfer of#@#oncogenes by uptake of apoptotic bodies.Proc Natl Acad Sci U S#@#A. 2001;98:6407–6411.

    Article  CAS  Google Scholar 

  140. Reiter I, Krammer B, Schwamberger G. Differential effect of apoptotic#@#versus necrotic tumor cells on macrophage antitumor activities.#@#J Immunol. 1999;163:1730–1732.

    CAS  PubMed  Google Scholar 

  141. Robson MG, Cook HT, Botto M, et al. Accelerated nephrotoxic#@#nephritis is exacerbated in C1q-deficient mice.J Immunol. 2001;#@#166:6820–6828.

    Article  CAS  PubMed  Google Scholar 

  142. van Lent PLEM, Licht R, Dijkman H, Holthuysen AEM, Berden JHM, van den Berg WB. Uptake of apoptotic leukocytes by synovial#@#lining macrophages inhibits immune complex-mediated#@#arthritis.J Leukoc Biol. 2001;70:708–714.

    PubMed  Google Scholar 

  143. Baumann I, Kolowos W, Voll RE, et al. Impaired uptake of apoptotic#@#cells into tingible body macrophages in germinal centers of#@#patients with systemic lupus erythematosus.Arthritis Rheum. 2002;#@#46:191–201.

    Article  PubMed  Google Scholar 

  144. Herrmann M, Voll RE, Zoller OM, Hagenhofer M, Ponner BB,#@#Kalden JR. Impaired phagocytosis of apoptotic cell material by#@#monocyte-derived macrophages from patients with systemic lupus#@#erythematosus.Arthritis Rheum. 1998;41:1241–1250.

    Article  CAS  PubMed  Google Scholar 

  145. Manfredi AA, Rovere P, Galati G, et al.Apoptotic cell clearance in#@#systemic lupus erythematosus: opsonization by antiphospholipid#@#antibodies.Arthritis Rheum. 1998;41:205–214.

    Article  CAS  PubMed  Google Scholar 

  146. Stach CM, Turnay X, Voll RE, et al. Treatment with annexin V#@#increases immunogenicity of apoptotic human T-cells in Balb/c#@#mice.Cell Death Differ. 2000;7:911–915.#@#147. Rosen A, Casciola-Rosen L. Clearing the way to mechanisms of#@#autoimmunity.Nat Med. 2001;7:664-665.#@#148. Khan TZ, Wagener JS, Bost T, Martinez J, Accurso FJ, Riches DW.#@#Early pulmonary inflammation in infants with cystic fibrosis.Am J#@#Respir Crit Care Med. 1995;151:1075-1082.#@#149. Utsugi T, Schroit AJ, Connor J, Bucana CD, Fidler IJ. Elevated#@#expression of phosphatidylserine in the outer membrane leaflet of#@#human tumor cells and recognition by activated human blood#@#monocytes.Cancer Res. 1991;51:3062-3066.#@#150. Kerr JFR, Wyllie AH, Currie AR. Apoptosis: a basic biological#@#phenomenon with wide-ranging implications in tissue kinetics.Br J#@#Cancer. 1972;26:239-257.#@#151. Wyllie AH, Kerr JFR, Currie AR. Cell death: the significance of#@#apoptosis.Int Rev Cytol. 1980;68:251-306.#@#152. Ginestra A, Miceli D, Dolo V, Romano FM, Vittorelli ML. Membrane#@#vesicles in ovarian cancer fluids: a new potential marker.#@#Anticancer Res. 1999;19:3439-3445.#@#153. Ginestra A, La Placa MD, Saldino F, Cassara D, Nagase H, Vittorelli#@#ML.The amount and proteolytic content of vesicles shed by#@#human cancer cell lines correlates with their in vitro invasiveness.#@#Anticancer Res. 1998;18:3433-3437.

    Article  CAS  PubMed  Google Scholar 

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  1. Program in Cell Biology, Department of Pediatrics;, National Jewish Medical and Research Center, 1400 Jackson Street, D509, 80206, Denver, Colorado, USA

    F. Jon Geske, Jenifer Monks, Lisa Lehman & Valerie A. Fadok

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  1. F. Jon Geske
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Correspondence to F. Jon Geske.

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Geske, F.J., Monks, J., Lehman, L. et al. The Role of the Macrophage in Apoptosis: Hunter, Gatherer, and Regulator. Int J Hematol 76, 16–26 (2002). https://doi.org/10.1007/BF02982714

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