Dead cell phagocytosis and innate immune checkpoint

  • Yoon, Kyoung Wan (Department of Biotechnology, Hoseo University)
  • Received : 2017.08.02
  • Published : 2017.10.31


The human body loses several billions of cells daily. When cells die in vivo, the corpse of each dead cell is immediately cleared. Specifically, dead cells are efficiently recognized and cleared by multiple types of neighboring phagocytes. Early research on cell death focused more on molecular mechanisms of cell death regulation while the cellular corpses were merely considered cellular debris. However, it has come to light that various biological stimuli following cell death are important for immune regulation. Clearance of normal dead cells occurs silently in immune tolerance. Exogenous or mutated antigens of malignant or infected cells can initiate adaptive immunity, thereby inducing immunogenicity by adjuvant signals. Several pathogens and cancer cells have strategies to limit the adjuvant signals and escape immune surveillance. In this review, we present an overview of the mechanisms of dead cell clearance and its immune regulations.


Dead cell clearance;Eat-me signal;Find-me signal;Immunogenic cell death;Innate immune checkpoint;Phagocytosis


  1. Arandjelovic S and Ravichandran KS (2015) Phagocytosis of apoptotic cells in homeostasis. Nat Immunol 16, 907-917
  2. Fond AM and Ravichandran KS (2016) Clearance of Dying Cells by Phagocytes: Mechanisms and Implications for Disease Pathogenesis. Adv Exp Med Biol 930, 25-49
  3. Elliott MR and Ravichandran KS (2016) The Dynamics of Apoptotic Cell Clearance. Dev Cell 38, 147-160
  4. Segawa K and Nagata S (2015) An Apoptotic 'Eat Me' Signal: Phosphatidylserine Exposure. Trends Cell Biol 25, 639-650
  5. van Engeland M, Nieland LJ, Ramaekers FC et al (1998) Annexin V-affinity assay: a review on an apoptosis detection system based on phosphatidylserine exposure. Cytometry 31, 1-9<1::AID-CYTO1>3.0.CO;2-R
  6. Segawa K, Kurata S, Yanagihashi Y et al (2014) Caspasemediated cleavage of phospholipid flippase for apoptotic phosphatidylserine exposure. Science 344, 1164-1168
  7. Suzuki J, Denning DP, Imanishi E et al (2013) Xk-related protein 8 and CED-8 promote phosphatidylserine exposure in apoptotic cells. Science 341, 403-406
  8. Green DR, Oguin TH and Martinez J (2016) The clearance of dying cells: table for two. Cell Death Differ 23, 915-926
  9. Elliott MR and Ravichandran KS (2010) Clearance of apoptotic cells: implications in health and disease. J Cell Biol 189, 1059-1070
  10. McIlroy D, Tanaka M, Sakahira H et al (2000) An auxiliary mode of apoptotic DNA fragmentation provided by phagocytes. Genes Dev 14, 549-558
  11. Lee CS, Penberthy KK, Wheeler KM et al (2016) Boosting Apoptotic Cell Clearance by Colonic Epithelial Cells Attenuates Inflammation In Vivo. Immunity 44, 807-820
  12. Sunaga H, Matsui H, Ueno M et al (2013) Deranged fatty acid composition causes pulmonary fibrosis in Elovl6-deficient mice. Nat Commun 4, 2563
  13. Poon IK, Lucas CD, Rossi AG et al (2014) Apoptotic cell clearance: basic biology and therapeutic potential. Nat Rev Immunol 14, 166-180
  14. Ravichandran KS and Lorenz U (2007) Engulfment of apoptotic cells: signals for a good meal. Nat Rev Immunol 7, 964-974
  15. Lauber K, Bohn E, Krober SM et al (2003) Apoptotic cells induce migration of phagocytes via caspase-3-mediated release of a lipid attraction signal. Cell 113, 717-730
  16. Scott RS, McMahon EJ, Pop SM et al (2001) Phagocytosis and clearance of apoptotic cells is mediated by MER. Nature 411, 207-211
  17. Yoon KW, Byun S, Kwon E et al (2015) Control of signaling-mediated clearance of apoptotic cells by the tumor suppressor p53. Science 349, 1261669
  18. Bonventre JV and Yang L (2011) Cellular pathophysiology of ischemic acute kidney injury. J Clin Invest 121, 4210-4221
  19. Bianconi E, Piovesan A, Facchin F et al (2013) An estimation of the number of cells in the human body. Ann Hum Biol 40, 463-471
  20. Nagata S, Hanayama R and Kawane K (2010) Autoimmunity and the clearance of dead cells. Cell 140, 619-630
  21. Hanayama R, Tanaka M, Miwa K et al (2002) Identification of a factor that links apoptotic cells to phagocytes. Nature 417, 182-187
  22. Rothlin CV, Carrera-Silva EA, Bosurgi L et al (2015) TAM receptor signaling in immune homeostasis. Annu Rev Immunol 33, 355-391
  23. Freeman GJ, Casasnovas JM, Umetsu DT et al (2010) TIM genes: a family of cell surface phosphatidylserine receptors that regulate innate and adaptive immunity. Immunol Rev 235, 172-189
  24. Miyanishi M, Tada K, Koike M et al (2007) Identification of Tim4 as a phosphatidylserine receptor. Nature 450, 435-439
  25. Nakayama M, Akiba H, Takeda K et al (2009) Tim-3 mediates phagocytosis of apoptotic cells and crosspresentation. Blood 113, 3821-3830
  26. Kinchen JM and Ravichandran KS (2008) Phagocytic signaling: you can touch, but you can't eat. Curr Biol 18, R521-524
  27. Chao MP, Alizadeh AA, Tang C et al (2010) Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell 142, 699-713
  28. Edris B, Weiskopf K, Volkmer AK et al (2012) Antibody therapy targeting the CD47 protein is effective in a model of aggressive metastatic leiomyosarcoma. Proc Natl Acad Sci U S A 109, 6656-6661
  29. Medina CB and Ravichandran KS (2016) Do not let death do us part: 'find-me' signals in communication between dying cells and the phagocytes. Cell Death Differ 23, 979-989
  30. Miyake Y, Asano K, Kaise H et al (2007) Critical role of macrophages in the marginal zone in the suppression of immune responses to apoptotic cell-associated antigens. J Clin Invest 117, 2268-2278
  31. Liu K, Iyoda T, Saternus M et al (2002) Immune tolerance after delivery of dying cells to dendritic cells in situ. J Exp Med 196, 1091-1097
  32. Asano K, Nabeyama A, Miyake Y et al (2011) CD169- positive macrophages dominate antitumor immunity by crosspresenting dead cell-associated antigens. Immunity 34, 85-95
  33. Chao MP, Jaiswal S, Weissman-Tsukamoto R et al (2010) Calreticulin is the dominant pro-phagocytic signal on multiple human cancers and is counterbalanced by CD47. Sci Transl Med 2, 63ra94
  34. Fujii S, Goto A and Shimizu K (2009) Antigen mRNAtransfected, allogeneic fibroblasts loaded with NKT-cell ligand confer antitumor immunity. Blood 113, 4262-4272
  35. Gordon S, Pluddemann A and Martinez Estrada F (2014) Macrophage heterogeneity in tissues: phenotypic diversity and functions. Immunol Rev 262, 36-55
  36. Qiu CH, Miyake Y, Kaise H et al (2009) Novel subset of CD8{alpha}+ dendritic cells localized in the marginal zone is responsible for tolerance to cell-associated antigens. J Immunol 182, 4127-4136
  37. Rovere-Querini P, Capobianco A, Scaffidi P et al (2004) HMGB1 is an endogenous immune adjuvant released by necrotic cells. EMBO Rep 5, 825-830
  38. Dumitriu IE, Baruah P, Valentinis B et al (2005) Release of high mobility group box 1 by dendritic cells controls T cell activation via the receptor for advanced glycation end products. J Immunol 174, 7506-7515
  39. Yamasaki S, Ishikawa E, Sakuma M et al (2008) Mincle is an ITAM-coupled activating receptor that senses damaged cells. Nat Immunol 9, 1179-1188
  40. Yagai T, Miyajima A and Tanaka M (2014) Semaphorin 3E secreted by damaged hepatocytes regulates the sinusoidal regeneration and liver fibrosis during liver regeneration. Am J Pathol 184, 2250-2259
  41. Gavrieli Y, Sherman Y and Ben-Sasson SA (1992) Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol 119, 493-501
  42. Nonomura K, Yamaguchi Y, Hamachi M et al (2013) Local apoptosis modulates early mammalian brain development through the elimination of morphogen-producing cells. Dev Cell 27, 621-634
  43. Pasparakis M and Vandenabeele P (2015) Necroptosis and its role in inflammation. Nature 517, 311-320
  44. Lamkanfi M and Dixit VM (2014) Mechanisms and functions of inflammasomes. Cell 157, 1013-1022
  45. Yang WS, SriRamaratnam R, Welsch ME et al (2014) Regulation of ferroptotic cancer cell death by GPX4. Cell 156, 317-331
  46. Vouri M and Hafizi S (2017) TAM Receptor Tyrosine Kinases in Cancer Drug Resistance. Cancer Res 77, 2775-2778
  47. Byun DJ, Wolchok JD, Rosenberg LM et al (2017) Cancer immunotherapy - immune checkpoint blockade and associated endocrinopathies. Nat Rev Endocrinol 13, 195-207
  48. DeRyckere D, Lee-Sherick AB, Huey MG et al (2017) UNC2025, a MERTK Small-Molecule Inhibitor, Is Therapeutically Effective Alone and in Combination with Methotrexate in Leukemia Models. Clin Cancer Res 23, 1481-1492
  49. Galluzzi L, Buque A, Kepp O et al (2017) Immunogenic cell death in cancer and infectious disease. Nat Rev Immunol 17, 97-111

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