Abstract
Engulfment by a phagocyte is the final commonevent in the life of most apoptotic cells. Phagocytosisof apoptotic bodies prior to their lysis prevents therelease of potentially toxic or immunogenicintracellular contents and activates an anti-inflammatoryresponse, at least in macrophages. We are beginning tounderstand the mechanisms by which macrophages and otherphagocytes recognize apoptotic cells in vitro, but we are a long way from determining theirrelative importance in vivo. The involuting mammarygland undergoes massive cell loss by apoptosis. Thedying alveolar epithelial cells can be shed into the lumen or can be phagocytosed by macrophages andviable epithelial cells. Yet we know virtually nothingabout the mechanisms mediating recognition and uptake inthe mammary gland. It is likely that clearance of apoptotic cells is critical to normalremodeling of the gland in preparation for the next waveof lactation. The mammary gland, therefore, provides anideal organ in which to study the mechanisms and consequences of apoptotic cell clearance invivo.
Similar content being viewed by others
REFERENCES
J. F. R. Kerr, A. H. Wyllie, and A. R. Currie (1972). Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics. Brit. J. Cancer 26:239–257.
A. H. Wyllie, J. F. R. Kerr, and A. R. Currie (1980). Cell death: The significance of apoptosis. Int. Rev. Cytol. 68:251–306.
M. J. Arends and A. H. Wyllie (1991). Apoptosis: Mechanisms and roles in pathology. Int. Rev. Exp. Pathol. 32:223–254.
J. J. Cohen, R. C. Duke, V. A. Fadok, and K. S. Sellins (1992). Apoptosis and programmed cell death in immunity. Ann. Rev. Immunol. 10:267–293.
M. C. Raff (1992). Social controls on cell survival and cell death. Nature 356:397–400.
N. I. Walker, R. E. Bennett, and J. F. R. Kerr (1989). Cell death by apoptosis during involution of the lactating breast in mice and rats. Am. J. Anat. 185:19–32.
R. Strange, L. Feng, S. Saurer, A. Burkhardt, and R. R. Friis (1992). Apoptotic cell death and tissue remodeling during mouse mammary gland involution. Development 115:49–58.
W. Bielke, G. Ke, Z. Feng, S. Bhurer, S. Saurer, and R. R. Friis (1997). Apoptosis in the rat mammary gland and ventral prostate: Detection of cell death-associated genes using a coincident-expression cloning approach. Cell Death Differ. 4: 114–124.
L. R. Lund, J. Romer, N. Thomasset, H. Solberg, C. Pyke, M. J. Bissell, K. Dane, and Z. Werb (1996). Two distinct phases of apoptosis in mammary gland involution: Proteinase-independent and-dependent pathways. Development 122: 181–193.
R. S. Guenette, H. B. Corbeil, J. Leger, K. Wong, V. Mezl, M. Mooibroek, and M. Tenniswood, (1994). Induction of gene expression during involution of the lactating mammary gland of the rat. J. Mol. Endocrinol. 12:47–60.
G. R. Merlo, N. Cella, and N. E. Hynes (1997). Apoptosis is accompanied by changes in bcl-2 and bax expression, induced by loss of attachment, and inhibited by specific extracellular matrix proteins in mammary epithelial cells. Cell Growth Differ. 8:251–260.
C. S. Atwood, M. Ikeda, and B. K. Vonderhaar (1995). Involution of mouse mammary glands in whole organ culture: A model for studying programmed cell death. Biochem. Biophys. Res. Commun. 207:860–867.
J. Savill (1997). Recognition and phagocytosis of cell undergoing apoptosis. Br. Med. Bull. 53:491–508.
Y. Ren and J. Savill (1998). Apoptosis: The importance of being eaten. Cell Death Differ. 5:563–568.
V. A. Fadok and P. M. Henson (1998). Apoptosis: Getting rid of the bodies. Curr. Biol. 8:R693–R695.
R. E. Voll, M. Herrmann, E. A. Roth, C. Stach, and J. R. Kalden (1997). Immunosuppressive effects of apoptotic cells. Nature 390:350–351.
V. A. Fadok, D. L. Bratton, A. Konowal, P. W. Freed, J. Y. Westcott, and P. M. Henson (1998). Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGFβ, PGE2, and PAF. J. Clin. Invest. 101:890–898.
Y. Gao, J. M. Herndon, H. Zhang, T. S. Griffith, and T. A. Ferguson (1998). Antiinflammatory effects of CD95 ligand (FasL)-induced apoptosis. J. Exp. Med. 188:887–896.
J. Ogasawara, R. Watanable-Fukunaga, M. Adachi, A. Matsuzawa, T. Kasugai, Y. Kitamura, N. Itho, T. Suda, and S. Nagata (1993). Lethal effect of the anti-Fas antibody in mice. Nature 364:806–809.
M. Herrmann, R. E. Voll, O. M. Zoller, M. Hagenhofer, B. B. Ponner, and J. R. Kalden (1998). Impaired phagocytosis of apoptotic cell material by monocyte-derived macrophages from patients with systemic lupus erythematosus. Arthritis Rheum. 41:1241–1250.
M. Botto, C. Dell' Agnola, A. E. Bygrave, E. M. Thompsonn, H. T. Cook, F. Petry, M. Loos, P. P. Pandolfi, and M. J. Walport (1998). Homozygmous C1q deficiency causes glomerulonephritis asssociated with multiple apoptotic bodies. Nat. Genet. 19:56–59.
S. L. Newman, J. E. Henson, and P. M. Henson (1982). Phagocytosis of senescent neutrophils by human monocyte-derived macrophages and rabbit inflammatory macrophages. J. Exp. Med. 156:430–442.
J. S. Savill, A. J. Wyllie, J. E. Henson, M. J. Walport, P. M. Henson, and C. Haslett (1989). Macrophage phagocytosis of aging neutrophils in inflammation. J. Clin. Invest. 83:865–875.
J. Savill, I. Dransfield, N. Hogg, and C. Haslett (1990). Vitronectin receptor-mediated phagocytosis of cells undergoing apoptosis. Nature 343:170–173.
J. Savill (1998). Phagocytic docking without shocking. Nature 392:442–443.
A. Devitt, O. D. Moffatt, C. Raykundalia, J. D. Capra, D. L. Simmons, and C. D. Gregory (1998). Human CD14 mediates recognition and phagocytosis of apoptotic cells. Nature 392:505–509.
E. Duvall, A. H. Wyllie, and R. G. Morris (1985). Macrophage recognition of cells undergoing programmed cell death (apoptosis). Immunology 56:351–358.
N. Platt, H. Suzuki, Y. Kurihara, T. Kodama, and S. Gordon (1996). Role for the class A macrophage scavenger reporter in the phagocytosis of apoptotic thymocytes in vitro. Proc. Natl. Acad. Sci. U.S.A. 93:12456–12460.
J. Savill, N. Hogg, Y. Ren, and C. Haslett (1992). Thrombospondin cooperates with CD36 and the vitronectin receptor in macrophage recognition of neutrophils undergoing apoptosis. J. Clin. Invest. 90:1513–1522.
M-F. Luciani and G. Chimini (1996). The ATP binding cassette transporter ABC1, is required for the engulfment of corpses generated by apoptotic cell death. EMBO J. 15:226–235.
V. Terpstra N. Kondratenko and S. Steinberg (1997). Macrophages lacking scavenger receptor A show a decrease in binding and uptake of acetylated low-density lipoprotein and of apoptotic thymocytes, but not of oxidatively damaged red blood cells. Proc. Natl. Acad. Sci. U.S.A. 94:8127–8131.
V. A. Fadok, J. S. Savill, C. Haslett, D. L. Bratton, D. E. Doherty, P. A. Campbell, and P. M. Henson (1992). Different populations of macrophages use either the vitronectin receptor or the phosphatidylserine receptor to recognize and remove apoptotic cells. J. Immunol. 149:4029–4035.
V. A. Fadok, D. R. Voelker, P. A. Campbell, J. J. Cohen, D. L. Bratton, and P. M. Henson (1992). Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J. Immunol. 148:2207–2216.
V. A. Fadok, D. J. Laszlo, P. W. Noble, L. Weinstein, D. W. H. Riches, and P. M. Henson (1993). Particle digestibility is required for induction of the phosphatidylserine recognition mechanism used by murine macrophages to phagocytose apoptotic cells. J. Immunol. 151:4274–4285.
V. A. Fadok, M. L. Warner, D. L. Bratton, and P. M. Henson (1998). CD36 is required for phagocytosis of apoptotic cells by human macrophages which utilize either a phosphatidylserine receptor or the vitronectin receptor (αvβ3). J. Immunol. 161:6250–6257.
D. Pradhan, S. Krahling, P. Williamson, and R. A. Schlegel (1997). Multiple systems for recognition of apoptotic lymphocytes by macrophages. Mol. Biol. Cell. 8:767–778.
Y-C. Wu and H. R. Horvitz (1998). C. elegans phagocytosis and cell-migration protein CED-5 is similar to human DOCK 180. Nature 392:501–504.
Q. A. Liu and M. O. Hengartner (1998). Candidate adaptor protein CED-6 promotes the engulfment of apoptotic cells in C. elegans. Cell 93:961–972.
Y-C. Wu and H. R. Horvitz (1998). The C. elegans cell corpse engulfment gene ced-7 encodes a protein similar to ABC transporters. Cell 93:9511–960.
L. Dini, F. Autuori, A. Lentini, S. Oliverio, and M. Piacentini (1992). The clearance of apoptotic cells in the liver is mediated by the asialoglycoprotein receptor. FEBS Lett. 296:174–178.
L. Dini, A. Lentini, G. D. Diez, M. Rocha, L. Falasca, and L. Serafino F. Vidal Vanclocha (1995). Phagocytosis of apoptotic bodies by liver endothelial cells. J. Cell Sci. 108:967–973.
L. Falasca, A. Bergamini, A. Serafino, C. Balabaud, and L. Dini (1996). Human Kupffer cell recognition and phagocytosis of apoptotic peripheral blood lymphocytes. Exp. Cell Res. 224:152–162.
D. A. Mower, D. W. Peckham, V. A. Illera, J. K. Fishbaugh, L. L. Stunz, and R. F. Ashman (1994). Decreased membrane phospholipid packing and decreased cell size precede DNA cleavage in mature mouse B cell apoptosis. J. Immunol. 152:4832–4841.
G. Koopman, C. P. M. Reutelingsperger, G. A. M. Kuijten, R. M. J. Keehnen, S. T. Pals, M. H. J. van Oers (1994). Annexin V for flow cytometric detection of phosphatidylserine expression on B cells undergoing apoptosis. Blood 84:1415–1420.
B. Verhoven, R. A. Schlegel, and P. Williamson (1995). Mechanisms of phosphatidylserine exposure, a phagocyte recognition signal on apoptotic T lymphocytes. J. Exp. Med. 182: 1597–1601.
S. J. Martin, C. P. M. Reutelingsperger, A. J. McGahon, J. A. Rader, R. C. A. A. van Schie, D. M. LaFace, and D. R. Green (1995). Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: Inhibition by overexpression of bcl-2 and abl. J. Exp. Med. 182:1545–1556.
C. H. E. Homburg, M. de Haas, A. E. G. Kr. von dem Borne, A. J. Verhoeven, C. P. M. Reutelingsperger, and D. Roos (1995). Human neutrophils lose their surface FcγRIII and acquire annexin V binding sites during apoptosis in vitro. Blood 85:532–540.
D. L. Bratton, V. A. Fadok, D. A. Richter, J. M. Kailey, L. A. Guthrie, and P. M. Henson (1997). Appearance of phosphatidylserine on apoptotic cells requires calcium-mediated nonspecific flip-flop and is enhanced by the loss of the aminophospholipid translocase. J. Biol. Chem. 272:26159–26165.
I. Vermes, C. Haanen, H. Steffens-Nakken, and C. Reutelingsperger (1995). A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labeled annexin V. J. Immunol. Meth. 184:39–51.
G. Zhang, V. Gurtu, S. R. Kain, and G. Yan (1997). Early detection of apoptosis using a fluorescent conjugate of annexin V. Biotechniques 23:525–531.
P-y. Wang, R. L. Kitchens, and R. S. Munford (1998). Phosphatidylinositides bind to plasma membrane CD14 and can prevent monocyte activation by bacterial lipopolysaccharide. J. Biol. Chem. 273:24309–24313.
P. K. Flora and C. D. Gregory (1994). Recognition of apoptotic cells by human macrophages: Inhibition by a monocyte/macro — phage-specific monoclonal antibody. Eur. J. Immunol. 24: 2625–2632.
S. P. Hart, G. J. Dougherty, C. Haslett, and I. Dransfield (1997). CD44 regulates phagocytosis of apoptotic neutrophil granulocytes, but not apoptotic lymphocytes, by human macrophages. J. Immunol. 159:919–925.
D. D. Roberts, D. M. Haverstick, V. M. Dixit, W. A. Frazier, S. A. Santoro, V. Ginsburg (1985). The platelet glycoprotein thrombospondin binds specifically to sulfated glycolipids. J. Biol. Chem. 260:9405–9411.
X. Sun, D. F. Mosher, and A. Rapraeger (1989). Heparan sulfate-mediated binding of epithelial cell surface proteoglycan to thrombospondin. J. Biol. Chem. 264:2885–2889.
L. C. Korb and J. M. Ahearn (1997). C1q binds directly and specifically to surface blebs of apoptotic human keratinocytes. Complement deficiency and systemic lupus erythematosus revisited. J. Immunol. 158:4525–4528.
B. E. Price, J. Rauch, M. A. Sia, M. T. Walsh, W. Lieberthal, H. Gilligan, T. O'Laughlin, J. S. Koh, and J. S. Levine (1996). Antiphospholipid autoantibodies bind to apoptotic, but not viable, thymocytes in a β2–glycoprotein 1–dependent manner. J. Immunol. 157:2201–2208.
A. A. Manfredi, P. Rovere, G. Galati, S. Heltai, E. Bozzolo, L. Soldini, J. Davoust, G. Balestrieri, A. Tincani, and M. G. Sabbadini (1998). Apoptotic cell clearance in systemic lupus erythematosus. I. Opsonization by antiphospholipid antibodies. Arthritis Rheum. 41:205–214.
A. A. Manfredi, P. Rovere, S. Heltai, G. Galati, G. Nebbia, A. Tincani, G. Balestrieri, and M. G. Sabbadini (1998). Apoptotic cell clearance in systemic lupus erythematosus. II. Role of β2–Glycoprotein I. Arthritis Rheum. 41:215–223.
K. Balasubramanian, J. Chandra, and A. J. Schroit (1997). Immune clearance of phosphatidylserine-expressing cells by phagocytes. J. Biol. Chem. 272:31113–31117.
K. Balasubramanian, and A. J. Schroit (1998). Characterization of phosphatidylserine-dependent b2–glycoprotein I macrophage interactions. J. Biol. Chem. 273:29272–29277.
F. Takizawa, S. Tsuji, and S. Nagasawa (1996). Enhancement of macrophage phagocytosis upon iC3b deposition on apoptotic cells. FEBS Lett. 397:269–272.
D. Mevorach, J. O. Mascarenhas, D. Gershov, and K. B. Elkon (1998). Complement-dependent clearance of apoptotic cells by human macrophages. J. Exp Med. 188:2313–2320.
J. Savill, J. Smith, C. Sarraf, Y. Ren, F. Abbott, and A. Rees (1992). Glomerular mesangial cells and inflammatory macrophages ingest neutrophils undergoing apoptosis. Kidney Intl. 42:924–936.
J. Hughes, Y. Liu, J. Van Damme, and J. Savill (1997). Human glomerular mesangial cell phagocytosis of apoptotic neutrophils. Meditation by a novel CD36–independent vitronectin receptor/thrombospondin recognition mechanism that is uncoupled from chemokine secretion. J. Immunol. 158:4389–4397.
M. R. Bennet, D. F. Gibson, S. M. Schwartz, J. F. Tait (1995). Binding and phagocytosis of apoptotic vascular smooth muscle cells is mediated in part by exposure of phosphatidylserine. Circ. Res. 77:1136–1142.
A. Shiratsuchi, M. Umeda, Y. Ohba, and Y. Nakanishi (1997). Recognition of phosphatidylserin e on the surface of apoptotic spermatogenic cells and subsequent phagocytosis by Sertoli cells of the rat. J. Biol. Chem. 272:2354–2358.
S. E. Hall, J. S. Savill, P. M. Henson, C. Haslett (1994). Apoptotic neutrophils are phagocytosed by fibroblasts with participation of the fibroblast vitronectin receptor and involvement of a mannose/fucose-sp ecific lectin. J. Immunol. 153:3218–3227.
R. S. Gomez, M. Pelka, A. C. Johannessen, O. P. Hornstein, and P. von den Driesch (1997). CD36 (OKM5) antigen expression on human mucosal epithelia is associated with keratinization type. J. Dermatol. 24:435–440.
M. Simon, I. Juhasz, M. Herlyn, and J. Hunyadi (1996). Thrombospondin receptor (CD36) expression of human keratinocytes during wound healing in a SCID mouse/human skin repair model. J. Dermatol. 23:305–309.
N. Aoki, T. Ishii, S. Ohira, Y. Yamaguchi, M. Negi, T. Adachi, R. Nakamura, and T. Matsuda (1997). Stage specific expression of milk fat globule membrane glycoproteins in mouse mammary gland: Comparison of MFG-E8, butyrophilin, and CD36 with a major milk protein, beta-casein. Biochim. Biophys. Acta 1334:182–190.
L. Berglund, T. E. Petersen, and J. T. Rasmussen (1996). Structural characterization of bovine CD36 from the milk fat globule membrane. Biochim. Biophys. Acta 1309:63–68.
Z. Abbadia, E. Vericel, P. Mathevet, N. Bertin, G. Panaye, and L. Frappart (1997). Fatty acid composition and CD36 expression in breast adipose tissue of premenopausal and post-menopausal women. Anticancer Res. 17:1217–1221.
A. G. S. Baillie, C. T. Coburn, and N. A. Abumrad (1996). Reversible binding of long-chain fatty acids to purified FAT, the adipose CD36 homolog. J. Membrane Biol. 153:75–81.
I. D. Silva, A. M. Salicioni, I. H. Russo, N. A. Higgy, L. H. Gebrim, and J. Russo (1997). Tamoxifen down-regulates CD36 messenger RNA levels in normal and neoplastic human breast tissues. Cancer Res. 57:378–381.
S. W. Ryeom, J. R. Sparrow, and R. L. Silverstein (1996). CD36 participates in the phagocytosis of rod outer segments by retinal pigment epithelium. J. Cell Sci. 109:387–395.
S. W. Ryeom, R. L. Silverstein, A. Scotto, and J. R. Sparrow (1996). Binding of anionic phospholipids to retinal pigment epithelium may be mediated by the scavenger receptor CD36. J. Biol. Chem. 271:20536–20539.
L. C. Meagher, J. S. Savill, A. Baker, R. W. Fuller, and C. Haslett (1992). Phagocytosis of apoptotic neutrophils does not induce macrophage release of thromboxane B2. J. Leukocyte Biol. 52:269–273.
M. Stern, J. Savill, and C. Haslett (1996). 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. 149:911–921.
M. L. Albert, B. Sauter, and N. Bhardwaj (1998). Dendritic cells acquire antigen from apoptotic cells and induce class Irestricted CTLs. Nature 392:86–89.
P. Rovere, C. Vallinoto, A. Bondanza, M. C. Crosti, M. Rescigno, P. Ricciardi-Castagnoli, C. Rugarli, and A. A. Manfredi (1998). Cutting edge: Bystander apoptosis triggers dendritic cell maturation and antigen-presenting function. J. Immunol. 161:4467–4471.
M. Albert, S. F. A. Pearce, L. M. Francisco, B. Sauter, P. Roy, R. L. Silverstein, and N. Bhardwaj (1998). Immature dentritic cells phagocytose apoptotic cells via αvβ5 and CD36, and cross-present antigens to cytotoxic T lymphocytes. J. Exp. Med. 188:1359–1368.
Y. Ren, R. L. Silverstein, J. Allen, and J. Savill (1995). CD36 gene transfer confers capacity for phagocytosis of cells undergoing apoptosis. J. Exp. Med. 181:1857–1862.
N. C. Franc, J-L. Dimarcq, M. Lagueux, J. Hoffmann, and R. A. B. Ezekowitz (1996). Croquemort, a novel Drosophila hemocyte/macrophage receptor that recognizes apoptotic cells. Immunity 4:431–443.
T. Nakano, Y. Ishimoto, J. Kishino, M. Umeda, K. Inoue, K. Nagata, K. Ohashi, K. Mizuno, and H. Arita (1997). Cell adhesion to phosphatidylserin e mediated by a product of growth arrest-specific gene 6. J. Biol. Chem. 272:29411–29414.
P. K. Flora and C. D. Gregory (1995). Recognition pathways in the interaction of macrophages with apoptotic B cells. Leukocyte Typing 5:1675–1677.
Rights and permissions
About this article
Cite this article
Fadok, V.A. Clearance: The Last and Often Forgotten Stage of Apoptosis. J Mammary Gland Biol Neoplasia 4, 203–211 (1999). https://doi.org/10.1023/A:1011384009787
Issue Date:
DOI: https://doi.org/10.1023/A:1011384009787