CoChat
Sign Up
Cited by 201Phagocytosis and Immune RegulationCell death mechanisms and regulationImmune Response and Inflammation

Macrophage Clearance of Apoptotic Cells: A Critical Assessment

Open access
Gordon, Siamon, Plüddemann, Annette·2018·Frontiers in Immunology
DOI 10.3389/fimmu.2018.00127PMC PMC5797608
Open this paper in CoChat — free accountOpen PDF

Abstract

As the body continues to grow and age, it becomes essential to maintain a balance between living and dying cells. Macrophages and Dendritic cells play a central role in discriminating among viable, apoptotic and necrotic cells, as selective and efficient phagocytes, without inducing inappropriate inflammation or immune responses. A great deal has been learnt concerning clearance receptors for modified and non-self ligands on potential targets, mediating their eventual uptake, disposal and replacement. In this essay, we assess current understanding of the phagocytic recognition of apoptotic cells within their tissue environment; we conclude that efferocytosis constitutes a more complex process than simply removal of corpses, with regulatory interactions between the target and effector cells, which determine the outcome of this homeostatic process. INTRODUCTION Programmed cell death, apoptosis, is closely linked to recognition and clearance by phagocytosis, resulting in anti-inflammatory and compensatory growth responses during foetal and adult life. Prolonged or incomplete containment and destruction during the apoptotic process can merge into secondary necrosis to bring about pro-inflammatory and pathological responses by phagocytes that are still poorly understood. Many aspects of this process are covered in excellent reviews by leading investigators, including Henson (1), Ravichandran (2), Nagata (3), Grinstein (4) and their colleagues, which should be consulted for detailed exposition. We have previously reviewed the process of phagocytosis in relation to infection and microbial recognition (5), emphasising its cell biology in model systems.We focus here on clearance of apoptotic cells in situ by heterogeneous tissue mononuclear phagocytes, in health and disease.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3389/fimmu.2018.00127

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Antibody recognizing Gr-1 (Ly-6G/Ly-6C) massively depleted phagocytes, which could not be fully compensated by resident macrophages or Gr-1(−) subsets.

    “Because efferocytosis is highly redundant both in terms of capable cell types and molecular machinery of engulfing dead cells27, another possible explanation is that antibody recognizing more broadly expressed Gr-1 (Ly-6G/Ly-6C, compared to CD11b) massively depleted phagocytes, which could not be fully compensated by resident macrophages or Gr-1(−) subsets.”

    From Hepatocyte mitochondria-derived danger signals directly activate hepatic stellate cells and drive progression of liver fibrosis (2020) · cites this paper as [27]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

The citation lists haven’t been fetched yet

References 79 · Cited by 201

Research works printed but not linked: 68

  1. [1]Henson PM. Cell removal: efferocytosis. Annu Rev Cell Dev Biol (2017) 33: 127– 44. 10.1146/annurev-cellbio-111315-125315 28613937 · DOI
  2. [2]Arandjelovic S Ravichandran KS. Phagocytosis of apoptotic cells in homeostasis. Nat Immunol (2015) 16: 907– 17. 10.1038/ni.3253 26287597 PMC4826466 · DOI · Paper page
  3. [3]Nagata S Tanaka M. Programmed cell death and the immune system. Nat Rev Immunol (2017) 17: 333– 40. 10.1038/nri.2016.153 28163302 · DOI
  4. [4]Lim JJ Grinstein S Roth Z. Diversity and versatility of phagocytosis: roles in innate immunity, tissue remodeling, and homeostasis. Front Cell Infect Microbiol (2017) 7: 191. 10.3389/fcimb.2017.00191 28589095 PMC5440456 · DOI
  5. [6]Wyllie AH Kerr JF Currie AR Cell death: the significance of apoptosis. Int Rev Cytol (1980) 68: 251– 306. 10.1016/S0074-7696(08)62312-8 7014501 · DOI
  6. [7]Wallach D Kang TB Kovalenko A. Concepts of tissue injury and cell death in inflammation: a historical perspective. Nat Rev Immunol (2014) 14: 51– 9. 10.1038/nri3561 24336099 · DOI
  7. [8]Underhill DM Gordon S Imhof BA Nunez G Bousso P Elie Metchnikoff (1845-1916): celebrating 100 years of cellular immunology and beyond. Nat Rev Immunol (2016) 16: 651– 6. 10.1038/nri.2016.89 27477126 · DOI
  8. [9]Yona S Gordon S. From the reticuloendothelial to mononuclear phagocyte system—the unaccounted years. Front Immunol (2015) 6: 328. 10.3389/fimmu.2015.00328 26191061 PMC4486871 · DOI
  9. [10]Pinto SM Hengartner MO. Cleaning up the mess: cell corpse clearance in Caenorhabditis elegans. Curr Opin Cell Biol (2012) 24: 881– 8. 10.1016/j.ceb.2012.11.002 23206434 · DOI
  10. [11]Freeman SA Grinstein S. Phagocytosis: how macrophages tune their non-professional counterparts. Curr Biol (2016) 26: R1279– 82. 10.1016/j.cub.2016.10.059 27997839 · DOI
  11. [12]deCathelineau AM Henson PM. The final step in programmed cell death: phagocytes carry apoptotic cells to the grave. Essays Biochem (2003) 39: 105– 17. 10.1042/bse0390105 14585077 · DOI
  12. [13]Vanden Berghe T Linkermann A Jouan-Lanhouet S Walczak H Vandenabeele P. Regulated necrosis: the expanding network of non-apoptotic cell death pathways. Nat Rev Mol Cell Biol (2014) 15: 135– 47. 10.1038/nrm3737 24452471 · DOI · Paper page
  13. [14]Cookson BT Brennan MA Pro-inflammatory programmed cell death. Trends Microbiol (2001) 9: 113– 4. 10.1016/S0966-842X(00)01936-3 11303500 · DOI
  14. [15]Brown GC Vilalta A Fricker M. Phagoptosis-cell death by phagocytosis-plays central roles in physiology, host defense and pathology. Curr Mol Med (2015) 15: 842– 51. 10.2174/156652401509151105130628 26511705 · DOI
  15. [16]Fearnhead HO Vandenabeele P Vanden Berghe T. How do we fit ferroptosis in the family of regulated cell death? Cell Death Differ (2017) 24: 1991– 8. 10.1038/cdd.2017.149 28984871 PMC5686356 · DOI
  16. [17]Joly E Hudrisier D What is trogocytosis and what is its purpose? Nat Immunol (2003) 4: 815 10.1038/ni0903-815 12942076 · DOI · Paper page
  17. [19]Mevorach D Trahtemberg U Krispin A Attalah M Zazoun J Tabib A What do we mean when we write “senescence,” “apoptosis,” “necrosis,” or “clearance of dying cells”? Ann N Y Acad Sci (2010) 1209: 1– 9. 10.1111/j.1749-6632.2010.05774.x 20958309 · DOI
  18. [20]Henson PM Bratton DL. Antiinflammatory effects of apoptotic cells. J Clin Invest (2013) 123: 2773– 4. 10.1172/JCI69344 23863635 PMC3696541 · DOI
  19. [21]Saas P Bonnefoy F Toussirot E Perruche S. Harnessing apoptotic cell clearance to treat autoimmune arthritis. Front Immunol (2017) 8: 1191. 10.3389/fimmu.2017.01191 29062314 PMC5640883 · DOI
  20. [22]Trahtemberg U Mevorach D. Apoptotic cells induced signaling for immune homeostasis in macrophages and dendritic cells. Front Immunol (2017) 8: 1356. 10.3389/fimmu.2017.01356 29118755 PMC5661053 · DOI
  21. [23]Gordon S Pluddemann A. Tissue macrophages: heterogeneity and functions. BMC Biol (2017) 15: 53. 10.1186/s12915-017-0392-4 28662662 PMC5492929 · DOI
  22. [24]Varol C Mildner A Jung S. Macrophages: development and tissue specialization. Annu Rev Immunol (2015) 33: 643– 75. 10.1146/annurev-immunol-032414-112220 25861979 · DOI · Paper page
  23. [25]Amit I Winter DR Jung S. The role of the local environment and epigenetics in shaping macrophage identity and their effect on tissue homeostasis. Nat Immunol (2016) 17: 18– 25. 10.1038/ni.3325 26681458 · DOI
  24. [27]Trahtemberg U Grau A Tabib A Atallah M Krispin A Mevorach D. Identification and characterization of two human monocyte-derived dendritic cell subpopulations with different functions in dying cell clearance and different patterns of cell death. PLoS One (2016) 11: e0162984. 10.1371/journal.pone.0162984 27690130 PMC5045195 · DOI
  25. [28]Wang J Kubes P. A reservoir of mature cavity macrophages that can rapidly invade visceral organs to affect tissue repair. Cell (2016) 165: 668– 78. 10.1016/j.cell.2016.03.009 27062926 · DOI · Paper page
  26. [29]Robbins CS Chudnovskiy A Rauch PJ Figueiredo JL Iwamoto Y Gorbatov R Extramedullary hematopoiesis generates Ly-6C(high) monocytes that infiltrate atherosclerotic lesions. Circulation (2012) 125: 364– 74. 10.1161/CIRCULATIONAHA.111.061986 22144566 PMC3263762 · DOI
  27. [31]A-Gonzalez N Quintana JA Garcia-Silva S Mazariegos M Gonzalez de la Aleja A Nicolas-Avila JA Phagocytosis imprints heterogeneity in tissue-resident macrophages. J Exp Med (2017) 214: 1281– 96. 10.1084/jem.20161375 28432199 PMC5413334 · DOI
  28. [33]Milde R Ritter J Tennent GA Loesch A Martinez FO Gordon S Multinucleated giant cells are specialized for complement-mediated phagocytosis and large target destruction. Cell Rep (2015) 13: 1937– 48. 10.1016/j.celrep.2015.10.065 26628365 PMC4675895 · DOI
  29. [34]Martinez FO Gordon S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep (2014) 6: 13. 10.12703/P6-13 24669294 PMC3944738 · DOI · Paper page
  30. [36]Savill J Dransfield I Gregory C Haslett C. A blast from the past: clearance of apoptotic cells regulates immune responses. Nat Rev Immunol (2002) 2: 965– 75. 10.1038/nri957 12461569 · DOI
  31. [37]Medina CB Ravichandran KS. Do not let death do us part: ‘find-me’ signals in communication between dying cells and the phagocytes. Cell Death Differ (2016) 23: 979– 89. 10.1038/cdd.2016.13 26891690 PMC4987731 · DOI
  32. [38]Wolf Y Boura-Halfon S Cortese N Haimon Z Sar Shalom H Kuperman Y Brown-adipose-tissue macrophages control tissue innervation and homeostatic energy expenditure. Nat Immunol (2017) 18: 665– 74. 10.1038/ni.3746 28459435 PMC5438596 · DOI
  33. [39]Kong Y Janssen BJ Malinauskas T Vangoor VR Coles CH Kaufmann R Structural basis for plexin activation and regulation. Neuron (2016) 91: 548– 60. 10.1016/j.neuron.2016.06.018 27397516 PMC4980550 · DOI
  34. [40]Weiskopf K Schnorr PJ Pang WW Chao MP Chhabra A Seita J Myeloid cell origins, differentiation, and clinical implications. Microbiol Spectr (2016) 4. 10.1128/microbiolspec 27763252 PMC5119546 · DOI
  35. [41]Oldenborg PA. CD47: a cell surface glycoprotein which regulates multiple functions of hematopoietic cells in health and disease. ISRN Hematol (2013) 2013: 614619. 10.1155/2013/614619 23401787 PMC3564380 · DOI
  36. [42]Penberthy KK Ravichandran KS. Apoptotic cell recognition receptors and scavenger receptors. Immunol Rev (2016) 269: 44– 59. 10.1111/imr.12376 26683144 PMC4685734 · DOI
  37. [43]Segawa K Nagata S. An apoptotic ‘eat me’ signal: phosphatidylserine exposure. Trends Cell Biol (2015) 25: 639– 50. 10.1016/j.tcb.2015.08.003 26437594 · DOI
  38. [44]Platt N Haworth R Darley L Gordon S. The many roles of the class A macrophage scavenger receptor. Int Rev Cytol (2002) 212: 1– 40. 10.1016/S0074-7696(01)12002-4 11804035 · DOI
  39. [45]Han CZ Juncadella IJ Kinchen JM Buckley MW Klibanov AL Dryden K Macrophages redirect phagocytosis by non-professional phagocytes and influence inflammation. Nature (2016) 539: 570– 4. 10.1038/nature20141 27820945 PMC5799085 · DOI
  40. [46]Wood W Turmaine M Weber R Camp V Maki RA McKercher SR Mesenchymal cells engulf and clear apoptotic footplate cells in macrophageless PU.1 null mouse embryos. Development (2000) 127: 5245– 52. 11076747
  41. [47]Goodridge HS Reyes CN Becker CA Katsumoto TR Ma J Wolf AJ Activation of the innate immune receptor Dectin-1 upon formation of a ‘phagocytic synapse’. Nature (2011) 472: 471– 5. 10.1038/nature10071 21525931 PMC3084546 · DOI
  42. [48]Wood W Martin P. Macrophage functions in tissue patterning and disease: new insights from the fly. Dev Cell (2017) 40: 221– 33. 10.1016/j.devcel.2017.01.001 28171746 PMC5300050 · DOI
  43. [49]Levin R Hammond GR Balla T De Camilli P Fairn GD Grinstein S. Multiphasic dynamics of phosphatidylinositol 4-phosphate during phagocytosis. Mol Biol Cell (2017) 28: 128– 40. 10.1091/mbc.E16-06-0451 28035045 PMC5221617 · DOI
  44. [50]Kay JG Grinstein S. Phosphatidylserine-mediated cellular signaling. Adv Exp Med Biol (2013) 991: 177– 93. 10.1007/978-94-007-6331-9_10 23775696 · DOI
  45. [51]Billings EA Lee CS Owen KA D’Souza RS Ravichandran KS Casanova JE. The adhesion GPCR BAI1 mediates macrophage ROS production and microbicidal activity against gram-negative bacteria. Sci Signal (2016) 9: ra14. 10.1126/scisignal.aac6250 26838550 PMC4894535 · DOI
  46. [52]Hamann J Hsiao CC Lee CS Ravichandran KS Lin HH. Adhesion GPCRs as modulators of immune cell function. Handb Exp Pharmacol (2016) 234: 329– 50. 10.1007/978-3-319-41523-9_15 27832495 · DOI
  47. [53]Levin R Grinstein S Canton J. The life cycle of phagosomes: formation, maturation, and resolution. Immunol Rev (2016) 273: 156– 79. 10.1111/imr.12439 27558334 · DOI
  48. [54]Lavin Y Winter D Blecher-Gonen R David E Keren-Shaul H Merad M Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell (2014) 159: 1312– 26. 10.1016/j.cell.2014.11.018 25480296 PMC4437213 · DOI · Paper page
  49. [55]Roberts AW Lee BL Deguine J John S Shlomchik MJ Barton GM. Tissue-resident macrophages are locally programmed for silent clearance of apoptotic cells. Immunity (2017) 47: 913.e– 27.e. 10.1016/j.immuni.2017.10.006 29150239 PMC5728676 · DOI · Paper page
  50. [56]Baratin M Simon L Jorquera A Ghigo C Dembele D Nowak J T cell zone resident macrophages silently dispose of apoptotic cells in the lymph node. Immunity (2017) 47(349–62): e5. 10.1016/j.immuni.2017.07.019 28801233 · DOI
  51. [57]Bannard O Cyster JG. Germinal centers: programmed for affinity maturation and antibody diversification. Curr Opin Immunol (2017) 45: 21– 30. 10.1016/j.coi.2016.12.004 28088708 · DOI
  52. [58]Weavers H Evans IR Martin P Wood W. Corpse engulfment generates a molecular memory that primes the macrophage inflammatory response. Cell (2016) 165: 1658– 71. 10.1016/j.cell.2016.04.049 27212238 PMC4912690 · DOI
  53. [59]Moorlag S Roring RJ Joosten LAB Netea MG. The role of the interleukin-1 family in trained immunity. Immunol Rev (2018) 281: 28– 39. 10.1111/imr.12617 29248003 · DOI
  54. [60]Askew K Li K Olmos-Alonso A Garcia-Moreno F Liang Y Richardson P Coupled proliferation and apoptosis maintain the rapid turnover of microglia in the adult brain. Cell Rep (2017) 18: 391– 405. 10.1016/j.celrep.2016.12.041 28076784 PMC5263237 · DOI · Paper page
  55. [61]Fogarty CE Diwanji N Lindblad JL Tare M Amcheslavsky A Makhijani K Extracellular reactive oxygen species drive apoptosis-induced proliferation via Drosophila macrophages. Curr Biol (2016) 26: 575– 84. 10.1016/j.cub.2015.12.064 26898463 PMC4765900 · DOI
  56. [63]Brown GC Neher JJ. Microglial phagocytosis of live neurons. Nat Rev Neurosci (2014) 15: 209– 16. 10.1038/nrn3710 24646669 · DOI · Paper page
  57. [64]Kawane K Fukuyama H Kondoh G Takeda J Ohsawa Y Uchiyama Y Requirement of DNase II for definitive erythropoiesis in the mouse fetal liver. Science (2001) 292: 1546– 9. 10.1126/science.292.5521.1546 11375492 · DOI
  58. [65]Godwin JW Pinto AR Rosenthal NA. Macrophages are required for adult salamander limb regeneration. Proc Natl Acad Sci U S A (2013) 110: 9415– 20. 10.1073/pnas.1300290110 23690624 PMC3677454 · DOI · Paper page
  59. [67]Bryant DM Johnson K DiTommaso T Tickle T Couger MB Payzin-Dogru D A tissue-mapped axolotl de novo transcriptome enables identification of limb regeneration factors. Cell Rep (2017) 18: 762– 76. 10.1016/j.celrep.2016.12.063 28099853 PMC5419050 · DOI
  60. [70]Rothlin CV Carrera-Silva EA Bosurgi L Ghosh S. TAM receptor signaling in immune homeostasis. Annu Rev Immunol (2015) 33: 355– 91. 10.1146/annurev-immunol-032414-112103 25594431 PMC4491918 · DOI
  61. [71]Chan PY Carrera-Silva EA De Kouchkovsky D Joannas LD Hao L Hu D The TAM family receptor tyrosine kinase TYRO3 is a negative regulator of type 2 immunity. Science (2016) 352: 99– 103. 10.1126/science.aaf1358 27034374 PMC4935984 · DOI
  62. [72]Larson SR Atif SM Gibbings SL Thomas SM Prabagar MG Danhorn T Ly6C(+) monocyte efferocytosis and cross-presentation of cell-associated antigens. Cell Death Differ (2016) 23: 997– 1003. 10.1038/cdd.2016.24 26990659 PMC4987733 · DOI
  63. [73]Campisi L Barbet G Ding Y Esplugues E Flavell RA Blander JM. Apoptosis in response to microbial infection induces autoreactive TH17 cells. Nat Immunol (2016) 17: 1084– 92. 10.1038/ni.3512 27455420 PMC5079524 · DOI
  64. [74]Kleinclauss F Perruche S Masson E de Carvalho Bittencourt M Biichle S Remy-Martin JP Intravenous apoptotic spleen cell infusion induces a TGF-beta-dependent regulatory T-cell expansion. Cell Death Differ (2006) 13: 41– 52. 10.1038/sj.cdd.4401699 15962005 PMC3448559 · DOI
  65. [75]Munoz LE Lauber K Schiller M Manfredi AA Herrmann M. The role of defective clearance of apoptotic cells in systemic autoimmunity. Nat Rev Rheumatol (2010) 6: 280– 9. 10.1038/nrrheum.2010.46 20431553 · DOI
  66. [76]Mevorach D Zuckerman T Reiner I Shimoni A Samuel S Nagler A Single infusion of donor mononuclear early apoptotic cells as prophylaxis for graft-versus-host disease in myeloablative HLA-matched allogeneic bone marrow transplantation: a phase I/IIa clinical trial. Biol Blood Marrow Transplant (2014) 20: 58– 65. 10.1016/j.bbmt.2013.10.010 24140121 · DOI
  67. [77]Baxter AE Russell RA Duncan CJ Moore MD Willberg CB Pablos JL Macrophage infection via selective capture of HIV-1-infected CD4+ T cells. Cell Host Microbe (2014) 16: 711– 21. 10.1016/j.chom.2014.10.010 25467409 PMC4271767 · DOI
  68. [78]Galluzzi L Buque A Kepp O Zitvogel L Kroemer G Immunogenic cell death in cancer and infectious disease. Nat Rev Immunol (2017) 17: 97– 111. 10.1038/nri.2016.107 27748397 · DOI · Paper page

Authors
Gordon, S., & Plüddemann, A.
Affiliations
  • Chang Gung University (TW)
  • University of Oxford (GB)
Corresponding author
Gordon, Siamon
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2018-01-30
Volume
9
Pages
127-127
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2018.00127
PMC
PMC5797608
OpenAlex
W2793584189
Cited by
201
References
79
Citations by year
2026: 16 · 2025: 15 · 2024: 30 · 2023: 17 · 2022: 31 · 2021: 29 · 2020: 30 · 2019: 24 · 2018: 9
FWCI
2.35
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords
efferocytosis, macrophages, dendritic cells, phagocytosis, programmed cell death, secondary necrosis, inflammation, tissue homeostasis
MeSH terms
Animals, Humans, Macrophages, Phagocytosis, Apoptosis

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review