The human body generates 10–100 billion cells every day, and the same number of cells die to maintain homeostasis in our body. Cells infected by bacteria or viruses also die. The cell death that occurs under physiological conditions mainly proceeds by apoptosis, which is a noninflammatory, or silent, process, while pathogen infection induces necroptosis or pyroptosis, which activates the immune system and causes inflammation. Dead cells generated by apoptosis are quickly engulfed by macrophages for degradation. Caspases are a large family of cysteine proteases that act in cascades. A cascade that leads to caspase 3 activation mediates apoptosis and is responsible for killing cells, recruiting macrophages, and presenting an “eat me” signal(s). When apoptotic cells are not efficiently engulfed by macrophages, they undergo secondary necrosis and release intracellular materials that represent a damage-associated molecular pattern, which may lead to a systemic lupus-like autoimmune disease.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Bianconi E, Piovesan A, Facchin F, Beraudi A, Casadei R. 1.  et al. 2013. An estimation of the number of cells in the human body. Ann. Hum. Biol. 40:463–71 [Google Scholar]
  2. Fuchs Y, Steller H. 2.  2011. Programmed cell death in animal development and disease. Cell 147:742–58 [Google Scholar]
  3. Bergmann O, Zdunek S, Felker A, Salehpour M, Alkass K. 3.  et al. 2015. Dynamics of cell generation and turnover in the human heart. Cell 161:1566–75 [Google Scholar]
  4. Marshman E, Booth C, Potten CS. 4.  2002. The intestinal epithelial stem cell. BioEssays 24:91–98 [Google Scholar]
  5. Spalding KL, Bhardwaj RD, Buchholz BA, Druid H, Frisén J. 5.  2005. Retrospective birth dating of cells in humans. Cell 122:133–43 [Google Scholar]
  6. Tak T, Tesselaar K, Pillay J, Borghans JAM, Koenderman L. 6.  2013. What's your age again? Determination of human neutrophil half-lives revisited. J. Leuk. Biol. 94:595–601 [Google Scholar]
  7. Casanova-Acebes M, Pitaval C, Weiss LA, Nombela-Arrieta C, Chèvre R. 7.  et al. 2013. Rhythmic modulation of the hematopoietic niche through neutrophil clearance. Cell 153:1025–35 [Google Scholar]
  8. Strydom N, Rankin SM. 8.  2013. Regulation of circulating neutrophil numbers under homeostasis and in disease. J. Innate Immun. 5:304–14 [Google Scholar]
  9. Connor J, Pak CC, Schroit AJ. 9.  1994. Exposure of phosphatidylserine in the outer leaflet of human red blood cells: relationship to cell density, cell age, and clearance by mononuclear cells. J. Biol. Chem. 269:2399–404 [Google Scholar]
  10. Williams JM, Duckworth CA, Burkitt MD, Watson AJM, Campbell BJ, Pritchard DM. 10.  2015. Epithelial cell shedding and barrier function: a matter of life and death at the small intestinal villus tip. Vet. Pathol. 52:445–55 [Google Scholar]
  11. Lockshin RA, Williams CM. 11.  1965. Programmed cell death—I. Cytology of degeneration in the intersegmental muscles of the pernyi silkmoth. J. Insect Physiol. 11:123–33 [Google Scholar]
  12. Kerr JF, Wyllie AH, Currie AR. 12.  1972. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 26:239–57 [Google Scholar]
  13. Wallach D, Kang TB, Dillon CP, Green DR. 13.  2016. Programmed necrosis in inflammation: toward identification of the effector molecules. Science 352:aaf2154 [Google Scholar]
  14. Abraham MC, Lu Y, Shaham S. 14.  2007. A morphologically conserved nonapoptotic program promotes linker cell death in Caenorhabditis elegans. . Dev. Cell 12:73–86 [Google Scholar]
  15. Berry DL, Baehrecke EH. 15.  2007. Growth arrest and autophagy are required for salivary gland cell degradation in Drosophila. . Cell 131:1137–48 [Google Scholar]
  16. deCathelineau AM, Henson PM. 16.  2003. The final step in programmed cell death: phagocytes carry apoptotic cells to the grave. Essays Biochem 39:105–17 [Google Scholar]
  17. Surh CD, Sprent J. 17.  1994. T-cell apoptosis detected in situ during positive and negative selection in the thymus. Nature 372:100–3 [Google Scholar]
  18. Medina CB, Ravichandran KS. 18.  2016. Do not let death do us part: “find-me” signals in communication between dying cells and the phagocytes. Cell Death Differ 23:979–89 [Google Scholar]
  19. Nagata S, Hanayama R, Kawane K. 19.  2010. Autoimmunity and the clearance of dead cells. Cell 140:619–30 [Google Scholar]
  20. Yuan J, Shaham S, Ledoux S, Ellis HM, Horvitz HR. 20.  1993. The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1β-converting enzyme. Cell 75:641–52 [Google Scholar]
  21. Crawford ED, Wells JA. 21.  2011. Caspase substrates and cellular remodeling. Annu. Rev. Biochem. 80:1055–87 [Google Scholar]
  22. Alnemri ES, Livingston DJ, Nicholson DW, Salvesen G, Thornberry NA. 22.  et al. 1996. Human ICE/CED-3 protease nomenclature. Cell 87:171 [Google Scholar]
  23. Julien O, Zhuang M, Wiita AP, O'Donoghue AJ, Knudsen GM. 23.  et al. 2016. Quantitative MS-based enzymology of caspases reveals distinct protein substrate specificities, hierarchies, and cellular roles. PNAS 113:E2001–10 [Google Scholar]
  24. Agard NJ, Maltby D, Wells JA. 24.  2010. Inflammatory stimuli regulate caspase substrate profiles. Mol. Cell. Proteom. 9:880–93 [Google Scholar]
  25. Riedl SJ, Salvesen GS. 25.  2007. The apoptosome: signalling platform of cell death. Nat. Rev. Mol. Cell Biol. 8:405–13 [Google Scholar]
  26. Czabotar PE, Lessene G, Strasser A, Adams JM. 26.  2014. Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat. Rev. Mol. Cell Biol. 15:49–63 [Google Scholar]
  27. Yuan S, Akey CW. 27.  2013. Apoptosome structure, assembly, and procaspase activation. Structure 21:501–15 [Google Scholar]
  28. Zhou M, Li Y, Hu Q, Bai X-C, Huang W. 28.  et al. 2015. Atomic structure of the apoptosome: mechanism of cytochrome c- and dATP-mediated activation of Apaf-1. Genes Dev 29:2349–61 [Google Scholar]
  29. Nagata S. 29.  1997. Apoptosis by death factor. Cell 88:355–65 [Google Scholar]
  30. Krammer PH. 30.  2000. CD95’s deadly mission in the immune system. Nature 407:789–95 [Google Scholar]
  31. Strasser A, Jost PJ, Nagata S. 31.  2009. The many roles of FAS receptor signaling in the immune system. Immunity 30:180–92 [Google Scholar]
  32. Schulte M, Reiss K, Lettau M, Maretzky T, Ludwig A. 32.  et al. 2007. ADAM10 regulates FasL cell surface expression and modulates FasL-induced cytotoxicity and activation-induced cell death. Cell Death Differ 14:1040–49 [Google Scholar]
  33. Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL. 33.  et al. 1997. A metalloproteinase disintegrin that releases tumour-necrosis factor-α from cells. Nature 385:729–33 [Google Scholar]
  34. O'Reilly LA, Tai L, Lee L, Kruse EA, Grabow S. 34.  et al. 2009. Membrane-bound Fas ligand only is essential for Fas-induced apoptosis. Nature 461:659–63 [Google Scholar]
  35. Tanaka M, Itai T, Adachi M, Nagata S. 35.  1998. Downregulation of Fas ligand by shedding. Nat. Med. 4:31–36 [Google Scholar]
  36. Matsumoto H, Murakami Y, Kataoka K, Notomi S, Mantopoulos D. 36.  et al. 2015. Membrane-bound and soluble Fas ligands have opposite functions in photoreceptor cell death following separation from the retinal pigment epithelium. Cell Death Dis 6:e1986 [Google Scholar]
  37. Hohlbaum AM, Moe S, Marshak-Rothstein A. 37.  2000. Opposing effects of transmembrane and soluble Fas ligand expression on inflammation and tumor cell survival. J. Exp. Med. 191:1209–20 [Google Scholar]
  38. Shiraishi T, Suzuyama K, Okamoto H, Mineta T, Tabuchi K. 38.  et al. 2004. Increased cytotoxicity of soluble Fas ligand by fusing isoleucine zipper motif. Biochem. Biophys. Res. Commun. 322:197–202 [Google Scholar]
  39. Walczak H, Degli-Esposti MA, Johnson RS, Smolak PJ, Waugh JY. 39.  et al. 1997. TRAIL-R2: a novel apoptosis-mediating receptor for TRAIL. EMBO J 16:5386–97 [Google Scholar]
  40. Holler N, Tardivel A, Kovacsovics-Bankowski M, Hertig S, Gaide O. 40.  et al. 2003. Two adjacent trimeric Fas ligands are required for Fas signaling and formation of a death-inducing signaling complex. Mol. Cell. Biol. 23:1428–40 [Google Scholar]
  41. Dhein J, Daniel PT, Trauth BC, Oehm A, Moller P, Krammer PH. 41.  1992. Induction of apoptosis by monoclonal antibody anti-APO-1 class switch variants is dependent on cross-linking of APO-1 cell surface antigens. J. Immunol. 149:3166–73 [Google Scholar]
  42. Tanaka M, Suda T, Takahashi T, Nagata S. 42.  1995. Expression of the functional soluble form of human Fas ligand in activated lymphocytes. EMBO J 14:1129–35 [Google Scholar]
  43. Walter DE, Schmich K, Vogel S, Pick R, Kaufmann T. 43.  et al. 2008. Switch from type II to I Fas/CD95 death signaling on in vitro culturing of primary hepatocytes. Hepatology 48:1942–53 [Google Scholar]
  44. Walczak H. 44.  2013. Death receptor–ligand systems in cancer, cell death, and inflammation. CSH Perspect. Biol. 5:a008698 [Google Scholar]
  45. Lavrik IN, Krammer PH. 45.  2012. Regulation of CD95/Fas signaling at the DISC. Cell Death Differ 19:36–41 [Google Scholar]
  46. Dickens LS, Boyd RS, Jukes-Jones R, Hughes MA, Robinson GL. 46.  et al. 2012. A death effector domain chain disc model reveals a crucial role for caspase-8 chain assembly in mediating apoptotic cell death. Mol. Cell 47:291–305 [Google Scholar]
  47. Schleich K, Warnken U, Fricker N, Öztürk S, Richter P. 47.  et al. 2012. Stoichiometry of the CD95 death-inducing signaling complex: experimental and modeling evidence for a death effector domain chain model. Mol. Cell 47:306–19 [Google Scholar]
  48. Jost PJ, Grabow S, Gray D, McKenzie MD, Nachbur U. 48.  et al. 2009. XIAP discriminates between type I and type II FAS-induced apoptosis. Nature 460:1035–39 [Google Scholar]
  49. Schüngel S, Buitrago-Molina LE, Nalapareddy PD, Lebofsky M, Manns MP. 49.  et al. 2009. The strength of the Fas ligand signal determines whether hepatocytes act as type 1 or type 2 cells in murine livers. Hepatology 50:1558–66 [Google Scholar]
  50. Cullen SP, Martin SJ. 50.  2015. Fas and TRAIL ‘death receptors’ as initiators of inflammation: implications for cancer. Semin. Cell Dev. Biol. 39:26–34 [Google Scholar]
  51. Peter ME, Hadji A, Murmann AE, Brockway S, Putzbach W. 51.  et al. 2015. The role of CD95 and CD95 ligand in cancer. Cell Death Differ 22:549–59 [Google Scholar]
  52. Wyllie AH. 52.  1980. Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature 284:555–56 [Google Scholar]
  53. Fadok VA, Voelker DR, Campbell PA, Cohen JJ, Bratton DL, Henson PM. 53.  1992. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J. Immunol. 148:2207–16 [Google Scholar]
  54. Cossarizza A, Kalashnikova G, Grassilli E, Chiappelli F, Salvioli S. 54.  et al. 1994. Mitochondrial modifications during rat thymocyte apoptosis: a study at the single cell level. Exp. Cell Res. 214:323–30 [Google Scholar]
  55. Crawford ED, Seaman JE, Agard N, Hsu GW, Julien O. 55.  et al. 2013. The DegraBase: a database of proteolysis in healthy and apoptotic human cells. Mol. Cell. Proteom. 12:813–24 [Google Scholar]
  56. Coleman ML, Sahai EA, Yeo M, Bosch M, Dewar A, Olson MF. 56.  2001. Membrane blebbing during apoptosis results from caspase-mediated activation of ROCK I. Nat. Cell Biol. 3:339–45 [Google Scholar]
  57. Enari M, Sakahira H, Yokoyama H, Okawa K, Iwamatsu A, Nagata S. 57.  1998. A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature 391:43–50 [Google Scholar]
  58. Suzuki J, Denning DP, Imanishi E, Horvitz HR, Nagata S. 58.  2013. Xk-related protein 8 and CED-8 promote phosphatidylserine exposure in apoptotic cells. Science 341:403–6 [Google Scholar]
  59. Segawa K, Kurata S, Yanagihashi Y, Brummelkamp T, Matsuda F, Nagata S. 59.  2014. Caspase-mediated cleavage of phospholipid flippase for apoptotic phosphatidylserine exposure. Science 344:1164–68 [Google Scholar]
  60. Op den Kamp JA. 60.  1979. Lipid asymmetry in membranes. Annu. Rev. Biochem. 48:47–71 [Google Scholar]
  61. Balasubramanian K, Schroit AJ. 61.  2003. Aminophospholipid asymmetry: a matter of life and death. Annu. Rev. Physiol. 65:701–34 [Google Scholar]
  62. Andersen JP, Vestergaard AL, Mikkelsen SA, Mogensen LS, Chalat M, Molday RS. 62.  2016. P4-ATPases as phospholipid flippases—structure, function, and enigmas. Front. Physiol. 7:1632–23 [Google Scholar]
  63. Palmgren MG, Nissen P. 63.  2011. P-type ATPases. Annu. Rev. Biophys. 40:243–66 [Google Scholar]
  64. Segawa K, Kurata S, Nagata S. 64.  2016. Human type IV P-type ATPases that work as plasma membrane phospholipid flippases, and their regulation by caspase and calcium. J. Biol. Chem. 291:762–72 [Google Scholar]
  65. Martin SJ, Reutelingsperger CP, McGahon AJ, Rader JA, van Schie RC. 65.  et al. 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. 182:1545–56 [Google Scholar]
  66. Vermes I, Haanen C, Steffens-Nakken H, Reutelingsperger C. 66.  1995. A novel assay for apoptosis: flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled Annexin V. J. Immunol. Methods 184:39–51 [Google Scholar]
  67. Nakano M, Fukuda M, Kudo T, Matsuzaki N, Azuma T. 67.  et al. 2009. Flip-flop of phospholipids in vesicles: kinetic analysis with time-resolved small-angle neutron scattering. J. Phys. Chem. B 113:6745–48 [Google Scholar]
  68. Kornberg RD, McConnell HM. 68.  1971. Inside-outside transitions of phospholipids in vesicle membranes. Biochemistry 10:1111–20 [Google Scholar]
  69. Comfurius P, Williamson P, Smeets E, Schlegel R, Bevers E, Zwaal R. 69.  1996. Reconstitution of phospholipid scramblase activity from human blood platelets. Biochemistry 35:7631–34 [Google Scholar]
  70. Basse F, Stout JG, Sims PJ, Wiedmer T. 70.  1996. Isolation of an erythrocyte membrane protein that mediates Ca2+-dependent transbilayer movement of phospholipid. J. Biol. Chem. 271:17205–10 [Google Scholar]
  71. Wiedmer T, Zhou Q, Kwoh DY, Sims PJ. 71.  2000. Identification of three new members of the phospholipid scramblase gene family. Biochim. Biophys. Acta 1467:244–53 [Google Scholar]
  72. Wiedmer T, Zhao J, Nanjundan M, Sims P. 72.  2003. Palmitoylation of phospholipid scramblase 1 controls its distribution between nucleus and plasma membrane. Biochemistry 42:1227–33 [Google Scholar]
  73. Zhou Q, Zhao J, Wiedmer T, Sims PJ. 73.  2002. Normal hemostasis but defective hematopoietic response to growth factors in mice deficient in phospholipid scramblase 1. Blood 99:4030–38 [Google Scholar]
  74. Dong B, Zhou Q, Zhao J, Zhou A, Harty RN. 74.  et al. 2004. Phospholipid scramblase 1 potentiates the antiviral activity of interferon. J. Virol. 78:8983–93 [Google Scholar]
  75. Bateman A, Finn RD, Sims PJ, Wiedmer T, Biegert A, Söding J. 75.  2009. Phospholipid scramblases and Tubby-like proteins belong to a new superfamily of membrane tethered transcription factors. Bioinformatics 25:159–62 [Google Scholar]
  76. Arashiki N, Saito M, Koshino I, Kamata K, Hale J. 76.  et al. 2016. An unrecognized function of cholesterol: regulating the mechanism controlling membrane phospholipid asymmetry. Biochemistry 55:3504–13 [Google Scholar]
  77. Rayala S, Francis VG, Sivagnanam U, Gummadi SN. 77.  2014. N-terminal proline-rich domain is required for scrambling activity of human phospholipid scramblases. J. Biol. Chem. 289:13206–18 [Google Scholar]
  78. Suzuki J, Umeda M, Sims PJ, Nagata S. 78.  2010. Calcium-dependent phospholipid scrambling by TMEM16F. Nature 468:834–38 [Google Scholar]
  79. Whitlock JM, Hartzell HC. 79.  2017. Anoctamins/TMEM16 proteins: Chloride channels flirting with lipids and extracellular vesicles. Annu. Rev. Physiol. 79:119–43 [Google Scholar]
  80. Bevers EM, Williamson PL. 80.  2016. Getting to the outer leaflet: physiology of phosphatidylserine exposure at the plasma membrane. Physiol. Rev. 96:605–45 [Google Scholar]
  81. Suzuki J, Fujii T, Imao T, Ishihara K, Kuba H, Nagata S. 81.  2013. Calcium-dependent phospholipid scramblase activity of TMEM16 protein family members. J. Biol. Chem. 288:13305–16 [Google Scholar]
  82. Brunner JD, Lim NK, Schenck S, Duerst A, Dutzler R. 82.  2014. X-ray structure of a calcium-activated TMEM16 lipid scramblase. Nature 516:207–12 [Google Scholar]
  83. Tien J, Peters CJ, Wong XM, Cheng T, Jan YN. 83.  et al. 2014. A comprehensive search for calcium binding sites critical for TMEM16A calcium-activated chloride channel activity. eLife 3:e02772 [Google Scholar]
  84. Ishihara K, Suzuki J, Nagata S. 84.  2016. Role of Ca2+ in the stability and function of TMEM16F and 16K. Biochemistry 55:3180–88 [Google Scholar]
  85. Yu K, Whitlock JM, Lee K, Ortlund EA, Cui YY, Hartzell HC. 85.  2015. Identification of a lipid scrambling domain in ANO6/TMEM16F. eLife 4:e06901 [Google Scholar]
  86. Gyobu S, Miyata H, Ikawa M, Yamazaki D, Takeshima H. 86.  et al. 2015. A role of TMEM16E carrying a scrambling domain in sperm motility. Mol. Cell Biol. 36:645–59 [Google Scholar]
  87. Gyobu S, Ishihara K, Suzuki J, Segawa K, Nagata S. 87.  2017. Characterization of the scrambling domain of the TMEM16 family. PNAS 114:6274–79 [Google Scholar]
  88. Bethel NP, Grabe M. 88.  2016. Atomistic insight into lipid translocation by a TMEM16 scramblase. PNAS 113:14049–54 [Google Scholar]
  89. Fujii T, Sakata A, Nishimura S, Eto K, Nagata S. 89.  2015. TMEM16F is required for phosphatidylserine exposure and microvesicle release in activated mouse platelets. PNAS 112:12800–85 [Google Scholar]
  90. Brooks MB, Catalfamo JL, MacNguyen R, Tim D, Fancher S, McCardle JA. 90.  2015. A TMEM16F point mutation causes an absence of canine platelet TMEM16F and ineffective activation and death-induced phospholipid scrambling. J. Thromb. Haemost. 13:2240–52 [Google Scholar]
  91. Orrenius S, Zhivotovsky B, Nicotera P. 91.  2003. Regulation of cell death: the calcium–apoptosis link. Nat. Rev. Mol. Cell Biol. 4:552–65 [Google Scholar]
  92. van Kruchten R, Mattheij NJA, Saunders C, Feijge MAH, Swieringa F. 92.  et al. 2013. Both TMEM16F-dependent and TMEM16F-independent pathways contribute to phosphatidylserine exposure in platelet apoptosis and platelet activation. Blood 121:1850–57 [Google Scholar]
  93. Schoenwaelder SM, Yuan Y, Josefsson EC, White MJ, Yao Y. 93.  et al. 2009. Two distinct pathways regulate platelet phosphatidylserine exposure and procoagulant function. Blood 114:663–66 [Google Scholar]
  94. Williamson P, Christie A, Kohlin T, Schlegel RA, Comfurius P. 94.  et al. 2001. Phospholipid scramblase activation pathways in lymphocytes. Biochemistry 40:8065–72 [Google Scholar]
  95. Rivera A, Kam SY, Ho M, Romero JR, Lee S. 95.  2013. Ablation of the Kell/Xk complex alters erythrocyte divalent cation homeostasis. Blood Cell Mol. Dis. 50:80–85 [Google Scholar]
  96. Redman CM, Russo D, Lee S. 96.  1999. Kell, Kx and the McLeod syndrome. Baillière's Clin. Haematol. 12:621–35 [Google Scholar]
  97. Suzuki J, Imanishi E, Nagata S. 97.  2016. Xkr8 phospholipid scrambling complex in apoptotic phosphatidylserine exposure. PNAS 113:9509–14 [Google Scholar]
  98. Suzuki J, Imanishi E, Nagata S. 98.  2014. Exposure of phosphatidylserine by Xk-related protein family members during apoptosis. J. Biol. Chem. 289:30257–67 [Google Scholar]
  99. Schroit AJ, Fidler IJ. 99.  1982. Effects of liposome structure and lipid composition on the activation of the tumoricidal properties of macrophages by liposomes containing muramyl dipeptide. Cancer Res 42:161–67 [Google Scholar]
  100. Tanaka Y, Schroit AJ. 100.  1983. Insertion of fluorescent phosphatidylserine into the plasma membrane of red blood cells. Recognition by autologous macrophages. J. Biol. Chem. 258:11335–43 [Google Scholar]
  101. Schroit AJ, Madsen JW, Tanaka Y. 101.  1985. In vivo recognition and clearance of red blood cells containing phosphatidylserine in their plasma membranes. J. Biol. Chem. 260:5131–38 [Google Scholar]
  102. Martin OC, Pagano RE. 102.  1987. Transbilayer movement of fluorescent analogs of phosphatidylserine and phosphatidylethanolamine at the plasma membrane of cultured cells: evidence for a protein-mediated and ATP-dependent process(es). J. Biol. Chem. 262:5890–98 [Google Scholar]
  103. Krahling S, Callahan MK, Williamson P, Schlegel RA. 103.  1999. Exposure of phosphatidylserine is a general feature in the phagocytosis of apoptotic lymphocytes by macrophages. Cell Death Differ 6:183–89 [Google Scholar]
  104. Asano K, Miwa M, Miwa K, Hanayama R, Nagase H. 104.  et al. 2004. Masking of phosphatidylserine inhibits apoptotic cell engulfment and induces autoantibody production in mice. J. Exp. Med. 200:459–67 [Google Scholar]
  105. Segawa K, Suzuki J, Nagata S. 105.  2011. Constitutive exposure of phosphatidylserine on viable cells. PNAS 108:19246–51 [Google Scholar]
  106. Darland-Ransom M, Wang X, Sun CL, Mapes J, Gengyo-Ando K. 106.  et al. 2008. Role of C. elegans TAT-1 protein in maintaining plasma membrane phosphatidylserine asymmetry. Science 320:528–31 [Google Scholar]
  107. Nagata S, Suzuki J, Segawa K, Fujii T. 107.  2016. Exposure of phosphatidylserine on the cell surface. Cell Death Differ 23:952–61 [Google Scholar]
  108. Chen Y-Z, Mapes J, Lee E-S, Skeen-Gaar RR, Xue D. 108.  2013. Caspase-mediated activation of Caenorhabditis elegans CED-8 promotes apoptosis and phosphatidylserine externalization. Nat. Commun. 4:1–9 [Google Scholar]
  109. Rogers C, Fernandes-Alnemri T, Mayes L, Alnemri D, Cingolani G, Alnemri ES. 109.  2016. Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death. Nat. Commun. 8:1–14 [Google Scholar]
  110. Wang Y, Gao W, Shi X, Ding J, Liu W. 110.  et al. 2017. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature 547:99–103 [Google Scholar]
  111. Kawane K, Fukuyama H, Yoshida H, Nagase H, Ohsawa Y. 111.  et al. 2003. Impaired thymic development in mouse embryos deficient in apoptotic DNA degradation. Nat. Immunol. 4:138–44 [Google Scholar]
  112. Hanayama R, Tanaka M, Miwa K, Shinohara A, Iwamatsu A, Nagata S. 112.  2002. Identification of a factor that links apoptotic cells to phagocytes. Nature 417:182–87 [Google Scholar]
  113. Miksa M, Komura H, Wu R, Shah KG, Wang P. 113.  2009. A novel method to determine the engulfment of apoptotic cells by macrophages using pHrodo succinimidyl ester. J. Immunol. Methods 342:71–77 [Google Scholar]
  114. Fadok VA, Bratton DL, Rose DM, Pearson A, Ezekewitz RA, Henson PM. 114.  2000. A receptor for phosphatidylserine-specific clearance of apoptotic cells. Nature 405:85–90 [Google Scholar]
  115. Wang X, Wu YC, Fadok VA, Lee MC, Gengyo-Ando K. 115.  et al. 2003. Cell corpse engulfment mediated by C. elegans phosphatidylserine receptor through CED-5 and CED-12. Science 302:1563–66 [Google Scholar]
  116. Li MO, Sarkisian MR, Mehal WZ, Rakic P, Flavell RA. 116.  2003. Phosphatidylserine receptor is required for clearance of apoptotic cells. Science 302:1560–63 [Google Scholar]
  117. Bose J, Gruber AD, Helming L, Schiebe S, Wegener I. 117.  et al. 2004. The phosphatidylserine receptor has essential functions during embryogenesis but not in apoptotic cell removal. J. Biol. 3:15 [Google Scholar]
  118. Chang B, Chen Y, Zhao Y, Bruick RK. 118.  2007. JMJD6 is a histone arginine demethylase. Science 318:444–47 [Google Scholar]
  119. Kwok J, O'Shea M, Hume DA, Lengeling A. 119.  2017. Jmjd6, a JmjC dioxygenase with many interaction partners and pleiotropic functions. Front. Genet. 8:32 [Google Scholar]
  120. Wolf A, Schmitz C, Böttger A. 120.  2007. Changing story of the receptor for phosphatidylserine-dependent clearance of apoptotic cells. EMBO Rep 8:465–69 [Google Scholar]
  121. Schlegel R, Williamson P. 121.  2007. P.S. to PS (phosphatidylserine)–pertinent proteins in apoptotic cell clearance. Sci. STKE 2007:pe57 [Google Scholar]
  122. Segawa K, Nagata S. 122.  2015. An apoptotic ‘eat me’ signal: phosphatidylserine exposure. Trends Cell Biol 25:649–50 [Google Scholar]
  123. Vandivier RW, Henson PM, Douglas IS. 123.  2015. Burying the dead. CHEST 129:1673–82 [Google Scholar]
  124. Cao L, Chang H, Shi X, Peng C, He Y. 124.  2016. Keratin mediates the recognition of apoptotic and necrotic cells through dendritic cell receptor DEC205/CD205. PNAS 113:13438–43 [Google Scholar]
  125. Atkin-Smith GK, Poon IK. 125.  2017. Disassembly of the dying: mechanisms and functions. Trends Cell Biol 27:151–62 [Google Scholar]
  126. Stubbs JD, Lekutis C, Singer KL, Bui A, Yuzuki D. 126.  et al. 1990. cDNA cloning of a mouse mammary epithelial cell surface protein reveals the existence of epidermal growth factor-like domains linked to factor VIII-like sequences. PNAS 87:8417–21 [Google Scholar]
  127. Hanayama R, Tanaka M, Miyasaka K, Aozasa K, Koike M. 127.  et al. 2004. Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice. Science 304:1147–50 [Google Scholar]
  128. Miyasaka K, Hanayama R, Tanaka M, Nagata S. 128.  2004. Expression of milk fat globule epidermal growth factor 8 in immature dendritic cells for engulfment of apoptotic cells. Eur. J. Immunol. 34:1414–22 [Google Scholar]
  129. Hanayama R, Nagata S. 129.  2005. Impaired involution of mammary glands in the absence of milk fat globule EGF factor 8. PNAS 102:16886–91 [Google Scholar]
  130. Nakaya M, Watari K, Tajima M, Nakaya T, Matsuda S. 130.  et al. 2017. Cardiac myofibroblast engulfment of dead cells facilitates recovery after myocardial infarction. J. Clin. Investig. 127:383–401 [Google Scholar]
  131. Yamaguchi H, Takagi J, Miyamae T, Yokota S, Fujimoto T. 131.  et al. 2008. Milk fat globule EGF factor 8 in the serum of human patients of systemic lupus erythematosus. J. Leuk. Biol. 83:1300–7 [Google Scholar]
  132. Peng Y, Elkon KB. 132.  2011. Autoimmunity in MFG-E8-deficient mice is associated with altered trafficking and enhanced cross-presentation of apoptotic cell antigens. J. Clin. Investig. 121:2221–41 [Google Scholar]
  133. Sakamoto K, Fukushima Y, Ito K, Matsuda M, Nagata S. 133.  et al. 2016. Osteopontin in spontaneous germinal centers inhibits apoptotic cell engulfment and promotes anti-nuclear antibody production in lupus-prone mice. J. Immunol. 197:2177–86 [Google Scholar]
  134. Miksa M, Wu R, Dong W, Das P, Yang D, Wang P. 134.  2006. Dendritic cell-derived exosomes containing milk fat globule epidermal growth factor-factor VIII attenuate proinflammatory responses in sepsis. Shock 25:586–93 [Google Scholar]
  135. Miksa M, Wu R, Dong W, Komura H, Amin D. 135.  et al. 2009. Immature dendritic cell-derived exosomes rescue septic animals via milk fat globule epidermal growth factor-factor VIII. J. Immunol 183:5983–90 [Google Scholar]
  136. Yamaguchi H, Fujimoto T, Nakamura S, Ohmura K, Mimori T. 136.  et al. 2010. Aberrant splicing of the milk fat globule-EGF factor 8 (MFG-E8) gene in human systemic lupus erythematosus. Eur. J. Immunol. 40:1778–85 [Google Scholar]
  137. Nikpay M, Goel A, Won H-H, Hall LM, Willenborg C. 137.  et al. 2015. A comprehensive 1,000 Genomes–based genome-wide association meta-analysis of coronary artery disease. Nat. Genet. 47:1121–30 [Google Scholar]
  138. Miyanishi M, Tada K, Koike M, Uchiyama Y, Kitamura T, Nagata S. 138.  2007. Identification of Tim4 as a phosphatidylserine receptor. Nature 450:435–39 [Google Scholar]
  139. Freeman GJ, Casasnovas JM, Umetsu DT, DeKruyff RH. 139.  2010. TIM genes: a family of cell surface phosphatidylserine receptors that regulate innate and adaptive immunity. Immunol. Rev. 235:172–89 [Google Scholar]
  140. Thornley TB, Fang Z, Balasubramanian S, Larocca RA, Gong W. 140.  et al. 2014. Fragile TIM-4–expressing tissue resident macrophages are migratory and immunoregulatory. J. Clin. Investig. 124:3443–54 [Google Scholar]
  141. Yanagihashi Y, Segawa K, Maeda R, Nabeshima Y, Nagata S. 141.  2017. Mouse macrophages show different requirements for phosphatidylserine receptor Tim4 in efferocytosis. PNAS 114:8800–5 [Google Scholar]
  142. Bonnardel J, Da Silva C, Henri S, Tamoutounour S, Chasson L. 142.  et al. 2015. Innate and adaptive immune functions of Peyer's patch monocyte-derived cells. Cell Rep 11:770–84 [Google Scholar]
  143. Nishi C, Toda S, Segawa K, Nagata S. 143.  2014. Tim4- and MerTK-mediated engulfment of apoptotic cells by mouse resident peritoneal macrophages. Mol. Cell. Biol. 34:1512–20 [Google Scholar]
  144. Ichimura T, Bonventre JV, Bailly V, Wei H, Hession CA. 144.  et al. 1998. Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury. J. Biol. Chem. 273:4135–42 [Google Scholar]
  145. Ichimura T, Asseldonk EJ, Humphreys BD, Gunaratnam L, Duffield JS, Bonventre JV. 145.  2008. Kidney injury molecule-1 is a phosphatidylserine receptor that confers a phagocytic phenotype on epithelial cells. J. Clin. Investig. 118:1657–68 [Google Scholar]
  146. Yang L, Brooks CR, Xiao S, Sabbisetti V, Yeung MY. 146.  et al. 2015. KIM-1–mediated phagocytosis reduces acute injury to the kidney. J. Clin. Investig. 125:1620–36 [Google Scholar]
  147. Nakayama M, Akiba H, Takeda K, Kojima Y, Hashiguchi M. 147.  et al. 2009. Tim-3 mediates phagocytosis of apoptotic cells and cross-presentation. Blood 113:3821–30 [Google Scholar]
  148. DeKruyff RH, Bu X, Ballesteros A, Santiago C, Chim YLE. 148.  et al. 2010. T cell/transmembrane, Ig, and mucin-3 allelic variants differentially recognize phosphatidylserine and mediate phagocytosis of apoptotic cells. J. Immunol. 184:1918–30 [Google Scholar]
  149. Hafizi S, Dahlbäck B. 149.  2006. Gas6 and protein S: vitamin K-dependent ligands for the Axl receptor tyrosine kinase subfamily. FEBS J 273:5231–44 [Google Scholar]
  150. Walker FJ. 150.  1980. Regulation of activated protein C by a new protein: a possible function for bovine protein S. J. Biol. Chem. 255:5521–24 [Google Scholar]
  151. Walker FJ. 151.  1981. Regulation of activated Protein C by Protein S: the role of phospholipid in Factor Va inactivation. J. Biol. Chem. 256:11128–31 [Google Scholar]
  152. Schneider C, King RM, Philipson L. 152.  1988. Genes specifically expressed at growth arrest of mammalian cells. Cell 54:787–93 [Google Scholar]
  153. Manfioletti G, Brancolini C, Avanzi G, Schneider C. 153.  1993. The protein encoded by a growth arrest-specific gene (gas6) is a new member of the vitamin K-dependent proteins related to protein S, a negative coregulator in the blood coagulation cascade. Mol. Cell. Biol. 13:4976–85 [Google Scholar]
  154. O'Bryan JP, Frye RA, Cogswell PC, Neubauer A, Kitch B. 154.  et al. 1991. axl, a transforming gene isolated from primary human myeloid leukemia cells, encodes a novel receptor tyrosine kinase. Mol. Cell. Biol. 11:5016–31 [Google Scholar]
  155. Graham DK, Dawson TL, Mullaney DL, Snodgrass HR, Earp HS. 155.  1994. Cloning and mRNA expression analysis of a novel human protooncogene, c-mer. . Cell Growth Differ 5:647–57 [Google Scholar]
  156. Polvi A, Armstrong E, Lai C, Lemke G, Huebner K. 156.  et al. 1993. The human TYRO3 gene and pseudogene are located in chromosome 15q14-q25. Gene 134:289–93 [Google Scholar]
  157. Lemke G. 157.  2013. Biology of the TAM receptors. CSH Perspect. Biol. 5:a009076 [Google Scholar]
  158. Rothlin CV, Carrera-Silva EA, Bosurgi L, Ghosh S. 158.  2014. TAM receptor signaling in immune homeostasis. Annu. Rev. Immunol. 33:355–91 [Google Scholar]
  159. Graham DK, DeRyckere D, Davies KD, Earp HS. 159.  2014. The TAM family: phosphatidylserine-sensing receptor tyrosine kinases gone awry in cancer. Nat. Rev. Cancer 14:769–85 [Google Scholar]
  160. Stitt TN, Conn G, Gore M, Lai C, Bruno J. 160.  et al. 1995. The anticoagulation factor protein S and its relative, Gas6, are ligands for the Tyro 3/Axl family of receptor tyrosine kinases. Cell 80:661–70 [Google Scholar]
  161. Varnum BC, Young C, Elliott G, Garcia A, Bartley TD. 161.  et al. 1995. Axl receptor tyrosine kinase stimulated by the vitamin K-dependent protein encoded by growth-arrest-specific gene 6. Nature 373:623–26 [Google Scholar]
  162. Nagata K, Ohashi K, Nakano T, Arita H, Zong C. 162.  et al. 1996. Identification of the product of growth arrest-specific gene 6 as a common ligand for Axl, Sky, and Mer receptor tyrosine kinases. J. Biol. Chem. 271:30022–27 [Google Scholar]
  163. Tsou W-I, Nguyen K-QN, Calarese DA, Garforth SJ, Antes AL. 163.  et al. 2014. Receptor tyrosine kinases, TYRO3, AXL, and MER, demonstrate distinct patterns and complex regulation of ligand-induced activation. J. Biol. Chem. 289:25750–63 [Google Scholar]
  164. Lew ED, Oh J, Burrola PG, Lax I, Zagórska A. 164.  et al. 2014. Differential TAM receptor-ligand-phospholipid interactions delimit differential TAM bioactivities. eLife 3:e03385 [Google Scholar]
  165. Nakano T, Ishimoto Y, Kishino J, Umeda M, Inoue K. 165.  et al. 1997. Cell adhesion to phosphatidylserine mediated by a product of growth arrest-specific gene 6. J. Biol. Chem. 272:29411–14 [Google Scholar]
  166. Anderson HA, Maylock CA, Williams JA, Paweletz CP, Shu H, Shacter E. 166.  2002. Serum-derived protein S binds to phosphatidylserine and stimulates the phagocytosis of apoptotic cells. Nat. Immunol. 4:87–91 [Google Scholar]
  167. Scott RS, McMahon EJ, Pop SM, Reap EA, Caricchio R. 167.  et al. 2001. Phagocytosis and clearance of apoptotic cells is mediated by MER. Nature 411:207–11 [Google Scholar]
  168. Cohen PL, Caricchio R, Abraham V, Camenisch TD, Jennette JC. 168.  et al. 2002. Delayed apoptotic cell clearance and lupus-like autoimmunity in mice lacking the c-mer membrane tyrosine kinase. J. Exp. Med. 196:135–40 [Google Scholar]
  169. Lu Q, Lemke G. 169.  2001. Homeostatic regulation of the immune system by receptor tyrosine kinases of the Tyro 3 family. Science 293:306–11 [Google Scholar]
  170. Camenisch TD, Koller BH, Earp HS, Matsushima GK. 170.  1999. A novel receptor tyrosine kinase, Mer, inhibits TNF-α production and lipopolysaccharide-induced endotoxic shock. J. Immunol. 162:3498–503 [Google Scholar]
  171. Sen P, Wallet MA, Yi Z, Huang Y, Henderson M. 171.  et al. 2007. Apoptotic cells induce Mer tyrosine kinase–dependent blockade of NF-κB activation in dendritic cells. Blood 109:653–60 [Google Scholar]
  172. Rothlin CV, Ghosh S, Zuniga EI, Oldstone MBA, Lemke G. 172.  2007. TAM receptors are pleiotropic inhibitors of the innate immune response. Cell 131:1124–36 [Google Scholar]
  173. Bosurgi L, Bernink JH, Delgado Cuevas V, Gagliani N, Joannas L. 173.  et al. 2013. Paradoxical role of the proto-oncogene Axl and Mer receptor tyrosine kinases in colon cancer. PNAS 110:13091–96 [Google Scholar]
  174. Park D, Hochreiter-Hufford A, Ravichandran K. 174.  2009. The phosphatidylserine receptor TIM-4 does not mediate direct signaling. Curr. Biol. 19:346–51 [Google Scholar]
  175. Somersan S, Bhardwaj N. 175.  2001. Tethering and tickling: a new role for the phosphatidylserine receptor. J. Cell Biol. 155:501–4 [Google Scholar]
  176. Park D, Tosello-Trampont A-C, Elliott MR, Lu M, Haney LB. 176.  et al. 2007. BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module. Nature 450:430–34 [Google Scholar]
  177. Nakahashi-Oda C, Tahara-Hanaoka S, Honda S, Shibuya K, Shibuya A. 177.  2012. Identification of phosphatidylserine as a ligand for the CD300a immunoreceptor. Biochem. Biophys. Res. Commun. 417:646–50 [Google Scholar]
  178. Simhadri VR, Andersen JF, Calvo E, Choi S-C, Coligan JE, Borrego F. 178.  2012. Human CD300a binds to phosphatidylethanolamine and phosphatidylserine, and modulates the phagocytosis of dead cells. Blood 119:2799–809 [Google Scholar]
  179. Murakami Y, Tian L, Voss OH, Margulies DH, Krzewski K, Coligan JE. 179.  2014. CD300b regulates the phagocytosis of apoptotic cells via phosphatidylserine recognition. Cell Death Differ 21:1746–57 [Google Scholar]
  180. Choi SC, Simhadri VR, Tian L, Gil-Krzewska A, Krzewski K. 180.  et al. 2011. Cutting edge: mouse CD300f (CMRF-35–like molecule-1) recognizes outer membrane-exposed phosphatidylserine and can promote phagocytosis. J. Immunol. 187:3483–87 [Google Scholar]
  181. Park S-Y, Jung M-Y, Lee S-J, Kang KB, Gratchev A. 181.  et al. 2009. Stabilin-1 mediates phosphatidylserine-dependent clearance of cell corpses in alternatively activated macrophages. J. Cell Sci. 122:3365–73 [Google Scholar]
  182. Park SY, Jung MY, Kim HJ, Lee SJ, Kim SY. 182.  et al. 2008. Rapid cell corpse clearance by stabilin-2, a membrane phosphatidylserine receptor. Cell Death Differ 15:192–201 [Google Scholar]
  183. He M, Kubo H, Morimoto K, Fujino N, Suzuki T. 183.  et al. 2011. Receptor for advanced glycation end products binds to phosphatidylserine and assists in the clearance of apoptotic cells. EMBO Rep 12:358–64 [Google Scholar]
  184. Friggeri A, Banerjee S, Biswas S, de Freitas A, Liu G. 184.  et al. 2011. Participation of the receptor for advanced glycation end products in efferocytosis. J. Immunol. 186:6191–98 [Google Scholar]
  185. Gaboriaud C, Frachet P, Thielens NM, Arlaud GJ. 185.  2011. The human C1q globular domain: structure and recognition of non-immune self ligands. Front. Immunol. 2:92 [Google Scholar]
  186. Das S, Owen KA, Ly KT, Park D, Black SG. 186.  et al. 2011. Brain angiogenesis inhibitor 1 (BAI1) is a pattern recognition receptor that mediates macrophage binding and engulfment of gram-negative bacteria. PNAS 108:2136–41 [Google Scholar]
  187. Izawa K, Yamanishi Y, Maehara A, Takahashi M, Isobe M. 187.  et al. 2012. The receptor LMIR3 negatively regulates mast cell activation and allergic responses by binding to extracellular ceramide. Immunity 37:827–39 [Google Scholar]
  188. Moreau C, Bally I, Chouquet A, Bottazzi B, Ghebrehiwet B. 188.  et al. 2016. Structural and functional characterization of a single-chain form of the recognition domain of complement protein C1q. Front. Immunol. 7:113–19 [Google Scholar]
  189. Hirose Y, Saijou E, Sugano Y, Takeshita F, Nishimura S. 189.  et al. 2012. Inhibition of Stabilin-2 elevates circulating hyaluronic acid levels and prevents tumor metastasis. PNAS 109:4263–68 [Google Scholar]
  190. Hori O, Brett J, Slattery T, Cao R, Zhang J. 190.  et al. 1995. The receptor for advanced glycation end products (RAGE) is a cellular binding site for amphoterin: mediation of neurite outgrowth and co-expression of rage and amphoterin in the developing nervous system. J. Biol. Chem. 270:25752–61 [Google Scholar]
  191. Mercer J, Schelhaas M, Helenius A. 191.  2010. Virus entry by endocytosis. Annu. Rev. Biochem. 79:803–33 [Google Scholar]
  192. Morizono K, Chen ISY. 192.  2014. Role of phosphatidylserine receptors in enveloped virus infection. J. Virol. 88:4275–90 [Google Scholar]
  193. Arandjelovic S, Ravichandran KS. 193.  2015. Phagocytosis of apoptotic cells in homeostasis. Nat. Immunol. 16:907–17 [Google Scholar]
  194. Arur S, Uche UE, Rezaul K, Fong M, Scranton V. 194.  et al. 2003. Annexin I is an endogenous ligand that mediates apoptotic cell engulfment. Dev. Cell 4:587–98 [Google Scholar]
  195. Gardai SJ, McPhillips KA, Frasch SC, Janssen WJ, Starefeldt A. 195.  et al. 2005. Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell 123:321–34 [Google Scholar]
  196. Oldenborg PA, Zheleznyak A, Fang YF, Lagenaur CF, Gresham HD, Lindberg FP. 196.  2000. Role of CD47 as a marker of self on red blood cells. Science 288:2051–54 [Google Scholar]
  197. Brown S, Heinisch I, Ross E, Shaw K, Buckley CD, Savill J. 197.  2002. Apoptosis disables CD31-mediated cell detachment from phagocytes promoting binding and engulfment. Nature 418:200–3 [Google Scholar]
  198. Weyd H, Abeler-Dörner L, Linke B, Mahr A, Jahndel V. 198.  et al. 2013. Annexin A1 on the surface of early apoptotic cells suppresses CD8+ T cell immunity. PLOS ONE 8:e62449 [Google Scholar]
  199. Blume KE, Soeroes S, Waibel M, Keppeler H, Wesselborg S. 199.  et al. 2009. Cell surface externalization of Annexin A1 as a failsafe mechanism preventing inflammatory responses during secondary necrosis. J. Immunol. 183:8138–47 [Google Scholar]
  200. Grewal T, Wason SJ, Enrich C, Rentero C. 200.  2016. Annexins—insights from knockout mice. Biol. Chem. 397:1–23 [Google Scholar]
  201. Tarr JM, Young PJ, Morse R, Shaw DJ, Haigh R. 201.  et al. 2010. A mechanism of release of calreticulin from cells during apoptosis. J. Mol. Biol. 401:799–812 [Google Scholar]
  202. Obeid M, Tesniere A, Ghiringhelli F, Fimia GM, Apetoh L. 202.  et al. 2007. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat. Med. 13:54–61 [Google Scholar]
  203. Tzelepis F, Verway M, Daoud J, Gillard J, Hassani-Ardakani K. 203.  et al. 2014. Annexin1 regulates DC efferocytosis and cross-presentation during Mycobacterium tuberculosis infection. J. Clin. Investig. 125:752–68 [Google Scholar]
  204. Henson PM, Bratton DL, Fadok VA. 204.  2001. Apoptotic cell removal. Curr. Biol. 11:R795–805 [Google Scholar]
  205. Barclay AN, van den Berg TK. 205.  2014. The interaction between signal regulatory protein alpha (SIRP α) and CD47: structure, function, and therapeutic target. Annu. Rev. Immunol. 32:25–50 [Google Scholar]
  206. Chao MP, Majeti R, Weissman IL. 206.  2011. Programmed cell removal: a new obstacle in the road to developing cancer. Nat. Rev. Cancer 12:58–67 [Google Scholar]
  207. Chao MP, Jaiswal S, Weissman-Tsukamoto R, Alizadeh AA, Gentles AJ. 207.  et al. 2010. Calreticulin is the dominant pro-phagocytic signal on multiple human cancers and is counterbalanced by CD47. Sci. Transl. Med. 2:63ra94 [Google Scholar]
  208. Liu X, Pu Y, Cron K, Deng L, Kline J. 208.  et al. 2015. CD47 blockade triggers T cell-mediated destruction of immunogenic tumors. Nat. Med. 21:1209–15 [Google Scholar]
  209. Willingham SB, Volkmer J-P, Gentles AJ, Sahoo D, Dalerba P. 209.  et al. 2012. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. PNAS 109:6662–67 [Google Scholar]
  210. Horrigan SK. 210. , Reprod. Proj. Cancer Biol. 2017. Replication study: The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. eLife 6:e18173 [Google Scholar]
  211. Tada K, Tanaka M, Hanayama R, Miwa K, Shinohara A. 211.  et al. 2003. Tethering of apoptotic cells to phagocytes through binding of CD47 to Src homology 2 domain-bearing protein tyrosine phosphatase substrate-1. J. Immunol. 171:5718–26 [Google Scholar]
  212. Nilsson A, Oldenborg P-A. 212.  2009. CD47 promotes both phosphatidylserine-independent and phosphatidylserine-dependent phagocytosis of apoptotic murine thymocytes by non-activated macrophages. Biochem. Biophys. Res. Commun. 387:58–63 [Google Scholar]
  213. Weiskopf K, Ring AM, Ho CCM, Volkmer JP, Levin AM. 213.  et al. 2013. Engineered SIRP variants as immunotherapeutic adjuvants to anticancer antibodies. Science 341:88–91 [Google Scholar]
  214. Sockolosky JT, Dougan M, Ingram JR, Ho CCM, Kauke MJ. 214.  et al. 2016. Durable antitumor responses to CD47 blockade require adaptive immune stimulation. PNAS 113:E2646–54 [Google Scholar]
  215. Bian Z, Shi L, Guo Y-L, Lv Z, Tang C. 215.  et al. 2016. Cd47-Sirpα interaction and IL-10 constrain inflammation-induced macrophage phagocytosis of healthy self-cells. PNAS 113:E5434–43 [Google Scholar]
  216. Nakaya M, Tanaka M, Okabe Y, Hanayama R, Nagata S. 216.  2006. Opposite effects of Rho family GTPases on engulfment of apoptotic cells by macrophages. J. Biol. Chem. 281:8836–42 [Google Scholar]
  217. Kim S-Y, Kim S, Bae D-J, Park S-Y, Lee G-Y. 217.  et al. 2017. Coordinated balance of Rac1 and RhoA plays key roles in determining phagocytic appetite. PLOS ONE 12:e0174603–19 [Google Scholar]
  218. Tosello-Trampont AC, Nakada-Tsukui K, Ravichandran KS. 218.  2003. Engulfment of apoptotic cells is negatively regulated by Rho-mediated signaling. J. Biol. Chem. 278:49911–19 [Google Scholar]
  219. Nakaya M, Kitano M, Matsuda M, Nagata S. 219.  2008. Spatiotemporal activation of Rac1 for engulfment of apoptotic cells. PNAS 105:9198–203 [Google Scholar]
  220. Kitano M, Nakaya M, Nakamura T, Nagata S, Matsuda M. 220.  2008. Imaging of Rab5 activity identifies essential regulators for phagosome maturation. Nature 453:241–45 [Google Scholar]
  221. Elliott MR, Ravichandran KS. 221.  2016. The dynamics of apoptotic cell clearance. Dev. Cell 38:147–60 [Google Scholar]
  222. Baumann I, Kolowos W, Voll RE, Manger B, Gaipl U. 222.  et al. 2002. Impaired uptake of apoptotic cells into tingible body macrophages in germinal centers of patients with systemic lupus erythematosus. Arthritis Rheum 46:191–201 [Google Scholar]
  223. Muñoz LE, Lauber K, Schiller M, Manfredi AA, Herrmann M. 223.  2010. The role of defective clearance of apoptotic cells in systemic autoimmunity. Nat. Rev. Rheumatol. 6:280–89 [Google Scholar]
  224. Miyanishi M, Segawa K, Nagata S. 224.  2012. Synergistic effect of Tim4 and MFG-E8 null mutations on the development of autoimmunity. Int. Immunol. 24:551–59 [Google Scholar]
  225. Galvan MD, Greenlee-Wacker MC, Bohlson SS. 225.  2012. C1q and phagocytosis: the perfect complement to a good meal. J. Leuk. Biol. 92:489–97 [Google Scholar]
  226. Botto M, Walport MJ. 226.  2002. C1q, autoimmunity and apoptosis. Immunobiology 205:395–406 [Google Scholar]
  227. Mitchell D, Pickering M, Warren J, Fossati-Jimack L, Cortes-Hernandez J. 227.  et al. 2002. C1q deficiency and autoimmunity: the effects of genetic background on disease expression. J. Immunol. 168:2538–43 [Google Scholar]
  228. Liang YY, Arnold T, Michlmayr A, Rainprecht D, Perticevic B. 228.  et al. 2014. Serum-dependent processing of late apoptotic cells for enhanced efferocytosis. Cell Death Dis 5:e1264 [Google Scholar]
  229. Colonna L, Parry GC, Panicker S, Elkon KB. 229.  2016. Uncoupling complement C1s activation from C1q binding in apoptotic cell phagocytosis and immunosuppressive capacity. Clin. Immunol. 163:84–90 [Google Scholar]
  230. Sisirak V, Sally B, D'Agati V, Martinez-Ortiz W, Özçakar ZB. 230.  et al. 2016. Digestion of chromatin in apoptotic cell microparticles prevents autoimmunity. Cell 166:88–101 [Google Scholar]
  231. Wilber A, O'Connor TP, Lu ML, Karimi A, Schneider MC. 231.  2003. Dnase1l3 deficiency in lupus-prone MRL and NZB/W F1 mice. Clin. Exp. Immunol. 134:46–52 [Google Scholar]
  232. Shichita T, Ito M, Morita R, Komai K, Noguchi Y. 232.  et al. 2017. MAFB prevents excess inflammation after ischemic stroke by accelerating clearance of damage signals through MSR1. Nat. Med. 23:723–32 [Google Scholar]
  233. Elkon KB, Santer DM. 233.  2012. Complement, interferon and lupus. Curr. Opin. Immunol. 24:665–70 [Google Scholar]
  234. Yang H, Biermann MH, Brauner JM, Liu Y, Zhao Y, Herrmann M. 234.  2016. New insights into neutrophil extracellular traps: mechanisms of formation and role in inflammation. Front. Immunol. 7:12–18 [Google Scholar]
  235. Boulé MW, Broughton C, Mackay F, Akira S, Marshak-Rothstein A, Rifkin IR. 235.  2004. Toll-like receptor 9–dependent and –independent dendritic cell activation by chromatin–immunoglobulin G complexes. J. Exp. Med. 199:1631–40 [Google Scholar]
  236. Lövgren T, Eloranta M-L, Båve U, Alm GV, Rönnblom L. 236.  2004. Induction of interferon-α production in plasmacytoid dendritic cells by immune complexes containing nucleic acid released by necrotic or late apoptotic cells and lupus IgG. Arthritis Rheumatol 50:1861–72 [Google Scholar]
  237. Marshak-Rothstein A. 237.  2006. Toll-like receptors in systemic autoimmune disease. Nat. Rev. Immunol. 6:823–35 [Google Scholar]
  238. Schrijvers DM, De Meyer GRY, Kockx MM, Herman AG, Martinet W. 238.  2005. Phagocytosis of apoptotic cells by macrophages is impaired in atherosclerosis. Arterioscler. Thromb. Vasc. 25:1256–61 [Google Scholar]
  239. Medeiros AI, Serezani CH, Lee SP, Peters-Golden M. 239.  2009. Efferocytosis impairs pulmonary macrophage and lung antibacterial function via PGE 2/EP2 signaling. J. Exp. Med. 206:61–68 [Google Scholar]
  240. Delbridge ARD, Grabow S, Strasser A, Vaux DL. 240.  2016. Thirty years of BCL-2: translating cell death discoveries into novel cancer therapies. Nat. Rev. Cancer 16:99–109 [Google Scholar]
  241. Nagata S. 241.  2005. DNA degradation in development and programmed cell death. Annu. Rev. Immunol. 23:853–75 [Google Scholar]
  242. Sebbagh M, Renvoizé C, Hamelin J, Riché N, Bertoglio J, Bréard J. 242.  2001. Caspase-3-mediated cleavage of ROCK I induces MLC phosphorylation and apoptotic membrane blebbing. Nat. Cell Biol. 3:346–52 [Google Scholar]
  243. Bao Q, Shi Y. 243.  2006. Apoptosome: a platform for the activation of initiator caspases. Cell Death Differ 14:56–65 [Google Scholar]
  244. Ehrenstein MR, Notley CA. 244.  2010. The importance of natural IgM: scavenger, protector and regulator. Nat. Rev. Immunol. 10:778–861 [Google Scholar]
  245. Mahajan A, Herrmann M, Muñoz LE. 245.  2016. Clearance deficiency and cell death pathways: a model for the pathogenesis of SLE. Front. Immunol. 7:107–12 [Google Scholar]

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error