Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The clearance of dead cells by efferocytosis

Abstract

Multiple modes of cell death have been identified, each with a unique function and each induced in a setting-dependent manner. As billions of cells die during mammalian embryogenesis and daily in adult organisms, clearing dead cells and associated cellular debris is important in physiology. In this Review, we present an overview of the phagocytosis of dead and dying cells, a process known as efferocytosis. Efferocytosis is performed by macrophages and to a lesser extent by other ‘professional’ phagocytes (such as monocytes and dendritic cells) and ‘non-professional’ phagocytes, such as epithelial cells. Recent discoveries have shed light on this process and how it functions to maintain tissue homeostasis, tissue repair and organismal health. Here, we outline the mechanisms of efferocytosis, from the recognition of dying cells through to phagocytic engulfment and homeostatic resolution, and highlight the pathophysiological consequences that can arise when this process is abrogated.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Efferocytosis is critical for tissue homeostasis.
Fig. 2: Cell-surface signals regulating efferocytosis.
Fig. 3: Phagocyte processing of a dying cell.

References

  1. Galluzzi, L. et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 25, 486–541 (2018). A useful set of definitions of diverse modes of cell death based on mechanisms rather than morphology.

    PubMed  PubMed Central  Google Scholar 

  2. Bergmann, A. & Steller, H. Apoptosis, stem cells, and tissue regeneration. Sci. Signal. 3, re8 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Suzanne, M. & Steller, H. Shaping organisms with apoptosis. Cell Death Differ. 20, 669–675 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Fuchs, Y. & Steller, H. Programmed cell death in animal development and disease. Cell 147, 742–758 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Blander, J. M. Death in the intestinal epithelium-basic biology and implications for inflammatory bowel disease. FEBS J. 283, 2720–2730 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Cummings, R. J. et al. Different tissue phagocytes sample apoptotic cells to direct distinct homeostasis programs. Nature 539, 565–569 (2016). A demonstration of the role of clearance of dead intestinal epithelial cells by intestinal macrophages and dendritic cells in controlling inflammation of the tissue.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Eckhart, L., Lippens, S., Tschachler, E. & Declercq, W. Cell death by cornification. Biochim. Biophys. Acta 1833, 3471–3480 (2013).

    Article  CAS  PubMed  Google Scholar 

  8. Florey, O., Krajcovic, M., Sun, Q. & Overholtzer, M. Entosis. Curr. Biol. 20, R88–R89 (2010).

    Article  CAS  PubMed  Google Scholar 

  9. Overholtzer, M. et al. A nonapoptotic cell death process, entosis, that occurs by cell-in-cell invasion. Cell 131, 966–979 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. Segawa, K. et al. Phospholipid flippases enable precursor B cells to flee engulfment by macrophages. Proc. Natl Acad. Sci. USA 115, 12212–12217 (2018). Genetic ablation of the phospholipid flippase ATP11C results in loss of developing B cells due to their engulfment.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Metayer, L. E., Vilalta, A., Burke, G. A. A. & Brown, G. C. Anti-CD47 antibodies induce phagocytosis of live, malignant B cells by macrophages via the Fc domain, resulting in cell death by phagoptosis. Oncotarget 8, 60892–60903 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Kerr, J. F., Wyllie, A. H. & Currie, A. R. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 26, 239–257 (1972).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Majno, G. & Joris, I. Apoptosis, oncosis, and necrosis. An overview of cell death. Am. J. Pathol. 146, 3–15 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Wyllie, A. H., Kerr, J. F. & Currie, A. R. Cell death: the significance of apoptosis. Int. Rev. Cytol. 68, 251–306 (1980).

    Article  CAS  PubMed  Google Scholar 

  15. Lauber, K. et al. Apoptotic cells induce migration of phagocytes via caspase-3-mediated release of a lipid attraction signal. Cell 113, 717–730 (2003).

    Article  CAS  PubMed  Google Scholar 

  16. Elliott, M. R. et al. Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature 461, 282–286 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Truman, L. A. et al. CX3CL1/fractalkine is released from apoptotic lymphocytes to stimulate macrophage chemotaxis. Blood 112, 5026–5036 (2008).

    Article  CAS  PubMed  Google Scholar 

  18. Elliott, M. R., Koster, K. M. & Murphy, P. S. Efferocytosis signaling in the regulation of macrophage inflammatory responses. J. Immunol. 198, 1387–1394 (2017).

    Article  CAS  PubMed  Google Scholar 

  19. Gude, D. R. et al. Apoptosis induces expression of sphingosine kinase 1 to release sphingosine-1-phosphate as a “come-and-get-me” signal. FASEB J. 22, 2629–2638 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Weigert, A. et al. Apoptotic cells promote macrophage survival by releasing the antiapoptotic mediator sphingosine-1-phosphate. Blood 108, 1635–1642 (2006).

    Article  CAS  PubMed  Google Scholar 

  21. Peter, C. et al. Release of lysophospholipid ‘find-me’ signals during apoptosis requires the ATP-binding cassette transporter A1. Autoimmunity 45, 568–573 (2012).

    Article  CAS  PubMed  Google Scholar 

  22. Luo, B. et al. Erythropoeitin signaling in macrophages promotes dying cell clearance and immune tolerance. Immunity 44, 287–302 (2016).

    Article  CAS  PubMed  Google Scholar 

  23. Kumar, H., Kawai, T. & Akira, S. Pathogen recognition by the innate immune system. Int. Rev. Immunol. 30, 16–34 (2011).

    Article  CAS  PubMed  Google Scholar 

  24. Akira, S., Uematsu, S. & Takeuchi, O. Pathogen recognition and innate immunity. Cell 124, 783–801 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Scaffidi, P., Misteli, T. & Bianchi, M. E. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418, 191–195 (2002).

    Article  CAS  PubMed  Google Scholar 

  26. Shi, Y., Evans, J. E. & Rock, K. L. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425, 516–521 (2003).

    Article  CAS  PubMed  Google Scholar 

  27. Shi, J., Gao, W. & Shao, F. Pyroptosis: gasdermin-mediated programmed necrotic cell death. Trends Biochem. Sci. 42, 245–254 (2017).

    Article  CAS  PubMed  Google Scholar 

  28. Liu, X., Zou, H., Slaughter, C. & Wang, X. DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. Cell 89, 175–184 (1997).

    Article  CAS  PubMed  Google Scholar 

  29. Enari, M. et al. A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature 391, 43–50 (1998).

    Article  CAS  PubMed  Google Scholar 

  30. Sakahira, H., Enari, M. & Nagata, S. Cleavage of CAD inhibitor in CAD activation and DNA degradation during apoptosis. Nature 391, 96–99 (1998).

    Article  CAS  PubMed  Google Scholar 

  31. Arandjelovic, S. & Ravichandran, K. S. Phagocytosis of apoptotic cells in homeostasis. Nat. Immunol. 16, 907–917 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhang, Q. et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464, 104–107 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hawes, M. C., Wen, F. & Elquza, E. Extracellular DNA: a bridge to cancer. Cancer Res. 75, 4260–4264 (2015).

    Article  CAS  PubMed  Google Scholar 

  34. Yang, Y. G., Lindahl, T. & Barnes, D. E. Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease. Cell 131, 873–886 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Paludan, S. R. & Bowie, A. G. Immune sensing of DNA. Immunity 38, 870–880 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Motwani, M., Pesiridis, S. & Fitzgerald, K. A. DNA sensing by the cGAS-STING pathway in health and disease. Nat. Rev. Genet. 20, 657–674 (2019).

    Article  CAS  PubMed  Google Scholar 

  37. Tanaka, Y. & Chen, Z. J. STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway. Sci. Signal. 5, ra20 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Kawane, K. et al. Requirement of DNase II for definitive erythropoiesis in the mouse fetal liver. Science 292, 1546–1549 (2001).

    Article  CAS  PubMed  Google Scholar 

  39. Gao, D. et al. Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases. Proc. Natl Acad. Sci. USA 112, E5699–E5705 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Baum, R. et al. STING contributes to abnormal bone formation induced by deficiency of DNase II in mice. Arthritis Rheumatol. 69, 460–471 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ahn, J., Gutman, D., Saijo, S. & Barber, G. N. STING manifests self DNA-dependent inflammatory disease. Proc. Natl Acad. Sci. USA 109, 19386–19391 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Cunha, L. D. et al. AIM2 ngages Acative but unprocessed caspase-1 to induce noncanonical activation of the NLRP3 inflammasome. Cell Rep. 20, 794–805 (2017).

    Article  CAS  PubMed  Google Scholar 

  43. Lugrin, J. & Martinon, F. The AIM2 inflammasome: sensor of pathogens and cellular perturbations. Immunol. Rev. 281, 99–114 (2018).

    Article  CAS  PubMed  Google Scholar 

  44. Stros, M. HMGB proteins: interactions with DNA and chromatin. Biochim. Biophys. Acta 1799, 101–113 (2010).

    Article  CAS  PubMed  Google Scholar 

  45. Yang, H., Wang, H., Chavan, S. S. & Andersson, U. High mobility group box protein 1 (HMGB1): the prototypical endogenous danger molecule. Mol. Med. 21, S6–S12 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Bertheloot, D. & Latz, E. HMGB1, IL-1alpha, IL-33 and S100 proteins: dual-function alarmins. Cell Mol. Immunol. 14, 43–64 (2017).

    Article  CAS  PubMed  Google Scholar 

  47. Bonaldi, T. et al. Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. EMBO J. 22, 5551–5560 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kazama, H. et al. Induction of immunological tolerance by apoptotic cells requires caspase-dependent oxidation of high-mobility group box-1 protein. Immunity 29, 21–32 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Venereau, E. et al. Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release. J. Exp. Med. 209, 1519–1528 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Wen, Q., Liu, J., Kang, R., Zhou, B. & Tang, D. The release and activity of HMGB1 in ferroptosis. Biochem. Biophys. Res. Commun. 510, 278–283 (2019).

    Article  CAS  PubMed  Google Scholar 

  51. Tirone, M. et al. High mobility group box 1 orchestrates tissue regeneration via CXCR4. J. Exp. Med. 215, 303–318 (2018). HMGB1, released on tissue injury, promotes the repair of liver and muscle via interaction with the chemokine receptor CXCR4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Rock, K. L. & Kono, H. The inflammatory response to cell death. Annu. Rev. Pathol. 3, 99–126 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Chen, C. J. et al. Identification of a key pathway required for the sterile inflammatory response triggered by dying cells. Nat. Med. 13, 851–856 (2007).

    Article  CAS  PubMed  Google Scholar 

  54. Eigenbrod, T., Park, J. H., Harder, J., Iwakura, Y. & Nunez, G. Cutting edge: critical role for mesothelial cells in necrosis-induced inflammation through the recognition of IL-1 alpha released from dying cells. J. Immunol. 181, 8194–8198 (2008).

    Article  CAS  PubMed  Google Scholar 

  55. Martin, S. J. Cell death and inflammation: the case for IL-1 family cytokines as the canonical DAMPs of the immune system. FEBS J. 283, 2599–2615 (2016). In this useful commentary, the idea that IL-1 family cytokines function as the ‘true’ DAMPs, released on cell death, is convincingly argued.

    Article  CAS  PubMed  Google Scholar 

  56. Idzko, M., Ferrari, D. & Eltzschig, H. K. Nucleotide signalling during inflammation. Nature 509, 310–317 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Chiu, Y. H. et al. A quantized mechanism for activation of pannexin channels. Nat. Commun. 8, 14324 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Chekeni, F. B. et al. Pannexin 1 channels mediate ‘find-me’ signal release and membrane permeability during apoptosis. Nature 467, 863–867 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Qu, Y. et al. Pannexin-1 is required for ATP release during apoptosis but not for inflammasome activation. J. Immunol. 186, 6553–6561 (2011).

    Article  CAS  PubMed  Google Scholar 

  60. Wang, Q. et al. Pyroptotic cells externalize eat-me and release find-me signals and are efficiently engulfed by macrophages. Int. Immunol. 25, 363–372 (2013).

    Article  CAS  PubMed  Google Scholar 

  61. Yang, D., He, Y., Munoz-Planillo, R., Liu, Q. & Nunez, G. Caspase-11 requires the pannexin-1 channel and the purinergic P2X7 pore to mediate pyroptosis and endotoxic shock. Immunity 43, 923–932 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Chen, J., Zhao, Y. & Liu, Y. The role of nucleotides and purinergic signaling in apoptotic cell clearance - implications for chronic inflammatory diseases. Front. Immunol. 5, 656 (2014).

    PubMed  PubMed Central  Google Scholar 

  63. Segawa, K. & Nagata, S. An apoptotic ‘eat me’ signal: phosphatidylserine exposure. Trends Cell Biol. 25, 639–650 (2015).

    Article  CAS  PubMed  Google Scholar 

  64. Suzuki, J., Denning, D. P., Imanishi, E., Horvitz, H. R. & Nagata, S. Xk-related protein 8 and CED-8 promote phosphatidylserine exposure in apoptotic cells. Science 341, 403–406 (2013).

    Article  CAS  PubMed  Google Scholar 

  65. Kloditz, K. & Fadeel, B. Three cell deaths and a funeral: macrophage clearance of cells undergoing distinct modes of cell death. Cell Death Discov. 5, 65 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Zargarian, S. et al. Phosphatidylserine externalization, “necroptotic bodies” release, and phagocytosis during necroptosis. PLoS Biol. 15, e2002711 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Ousingsawat, J., Schreiber, R. & Kunzelmann, K. TMEM16F/anoctamin 6 in ferroptotic cell death. Cancers 11, 625 (2019).

    Article  CAS  PubMed Central  Google Scholar 

  68. Fujii, T., Sakata, A., Nishimura, S., Eto, K. & Nagata, S. TMEM16F is required for phosphatidylserine exposure and microparticle release in activated mouse platelets. Proc. Natl Acad. Sci. USA 112, 12800–12805 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Suzuki, J., Umeda, M., Sims, P. J. & Nagata, S. Calcium-dependent phospholipid scrambling by TMEM16F. Nature 468, 834–838 (2010).

    Article  CAS  PubMed  Google Scholar 

  70. Hochreiter-Hufford, A. & Ravichandran, K. S. Clearing the dead: apoptotic cell sensing, recognition, engulfment, and digestion. Cold Spring Harb. Perspect. Biol. 5, a008748 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Wu, Y., Tibrewal, N. & Birge, R. B. Phosphatidylserine recognition by phagocytes: a view to a kill. Trends Cell Biol. 16, 189–197 (2006).

    Article  CAS  PubMed  Google Scholar 

  72. Geng, K. et al. Requirement of gamma-carboxyglutamic acid modification and phosphatidylserine binding for the activation of tyro3, Axl, and Mertk receptors by growth arrest-specific 6. Front. Immunol. 8, 1521 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Lee, H. N. et al. Dendritic cells expressing immunoreceptor CD300f are critical for controlling chronic gut inflammation. J. Clin. Invest. 127, 1905–1917 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Parks, B. W. et al. CD36, but not G2A, modulates efferocytosis, inflammation, and fibrosis following bleomycin-induced lung injury. J. Lipid Res. 54, 1114–1123 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Tait, J. F. & Smith, C. Phosphatidylserine receptors: role of CD36 in binding of anionic phospholipid vesicles to monocytic cells. J. Biol. Chem. 274, 3048–3054 (1999).

    Article  CAS  PubMed  Google Scholar 

  76. Szondy, Z., Sarang, Z., Kiss, B., Garabuczi, E. & Koroskenyi, K. Anti-inflammatory mechanisms triggered by apoptotic cells during their clearance. Front. Immunol. 8, 909 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Xu, W. et al. IL-10-producing macrophages preferentially clear early apoptotic cells. Blood 107, 4930–4937 (2006).

    Article  CAS  PubMed  Google Scholar 

  78. Fadok, V. A. et al. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J. Clin. Invest. 101, 890–898 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Freire-de-Lima, C. G. et al. Apoptotic cells, through transforming growth factor-beta, coordinately induce anti-inflammatory and suppress pro-inflammatory eicosanoid and NO synthesis in murine macrophages. J. Biol. Chem. 281, 38376–38384 (2006).

    Article  CAS  PubMed  Google Scholar 

  80. Voll, R. E. et al. Immunosuppressive effects of apoptotic cells. Nature 390, 350–351 (1997).

    Article  CAS  PubMed  Google Scholar 

  81. Kim, S. J., Gershov, D., Ma, X., Brot, N. & Elkon, K. B. I-PLA(2) activation during apoptosis promotes the exposure of membrane lysophosphatidylcholine leading to binding by natural immunoglobulin M antibodies and complement activation. J. Exp. Med. 196, 655–665 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Gardai, S. J. et al. Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell 123, 321–334 (2005).

    Article  CAS  PubMed  Google Scholar 

  83. Ogden, C. A. et al. C1q and mannose binding lectin engagement of cell surface calreticulin and CD91 initiates macropinocytosis and uptake of apoptotic cells. J. Exp. Med. 194, 781–795 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Oldenborg, P. A. et al. Role of CD47 as a marker of self on red blood cells. Science 288, 2051–2054 (2000).

    Article  CAS  PubMed  Google Scholar 

  85. Barkal, A. A. et al. CD24 signalling through macrophage Siglec-10 is a target for cancer immunotherapy. Nature 572, 392–396 (2019). Identification of the CD24–SIGLEC10 interaction as a ‘don’t-eat-me’ signal and its possible value in cancer therapy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Brown, S. et al. Apoptosis disables CD31-mediated cell detachment from phagocytes promoting binding and engulfment. Nature 418, 200–203 (2002).

    Article  CAS  PubMed  Google Scholar 

  87. Abram, C. L. & Lowell, C. A. Shp1 function in myeloid cells. J. Leukoc. Biol. 102, 657–675 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Barkal, A. A. et al. Engagement of MHC class I by the inhibitory receptor LILRB1 suppresses macrophages and is a target of cancer immunotherapy. Nat. Immunol. 19, 76–84 (2018). Identification of the MHC class I–LILRB1 interaction as a ‘don’t-eat-me’ signal and its possible value in cancer therapy.

    Article  CAS  PubMed  Google Scholar 

  89. Willingham, S. B. et al. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc. Natl Acad. Sci. USA 109, 6662–6667 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Werfel, T. A. & Cook, R. S. Efferocytosis in the tumor microenvironment. Semin. Immunopathol. 40, 545–554 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  91. Weiskopf, K. et al. Engineered SIRPalpha variants as immunotherapeutic adjuvants to anticancer antibodies. Science 341, 88–91 (2013).

    Article  CAS  PubMed  Google Scholar 

  92. Chao, M. P. et al. Calreticulin is the dominant pro-phagocytic signal on multiple human cancers and is counterbalanced by CD47. Sci. Transl Med. 2, 63ra94 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Azuma, Y., Nakagawa, H., Dote, K., Higai, K. & Matsumoto, K. Decreases in CD31 and CD47 levels on the cell surface during etoposide-induced Jurkat cell apoptosis. Biol. Pharm. Bull. 34, 1828–1834 (2011).

    Article  CAS  PubMed  Google Scholar 

  94. Richards, D. M. & Endres, R. G. The mechanism of phagocytosis: two stages of engulfment. Biophys. J. 107, 1542–1553 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Rosales, C. & Uribe-Querol, E. Phagocytosis: a fundamental process in immunity. Biomed. Res. Int. 2017, 9042851 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Ma, Z. et al. Regulation of Rac1 activation by the low density lipoprotein receptor-related protein. J. Cell Biol. 159, 1061–1070 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Park, D. et al. BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module. Nature 450, 430–434 (2007).

    Article  CAS  PubMed  Google Scholar 

  98. Green, D. R., Oguin, T. H. & Martinez, J. The clearance of dying cells: table for two. Cell Death Differ. 23, 915–926 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Elliott, M. R. & Ravichandran, K. S. The dynamics of apoptotic cell clearance. Dev. Cell 38, 147–160 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Sevajol, M. et al. The C-terminal polyproline-containing region of ELMO contributes to an increase in the life-time of the ELMO-DOCK complex. Biochimie 94, 823–828 (2012).

    Article  CAS  PubMed  Google Scholar 

  101. Waterborg, C. E. J. et al. Protective role of the MER tyrosine kinase via efferocytosis in rheumatoid arthritis models. Front. Immunol. 9, 742 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Nienhuis, H. L. et al. AGE and their receptor RAGE in systemic autoimmune diseases: an inflammation propagating factor contributing to accelerated atherosclerosis. Autoimmunity 42, 302–304 (2009).

    Article  CAS  PubMed  Google Scholar 

  103. Marie-Anais, F., Mazzolini, J., Herit, F. & Niedergang, F. Dynamin-actin cross talk contributes to phagosome formation and closure. Traffic 17, 487–499 (2016).

    Article  CAS  PubMed  Google Scholar 

  104. Stenmark, H. Rab GTPases as coordinators of vesicle traffic. Nat. Rev. Mol. Cell Biol. 10, 513–525 (2009).

    Article  CAS  PubMed  Google Scholar 

  105. Rink, J., Ghigo, E., Kalaidzidis, Y. & Zerial, M. Rab conversion as a mechanism of progression from early to late endosomes. Cell 122, 735–749 (2005).

    Article  CAS  PubMed  Google Scholar 

  106. Chavrier, P., Parton, R. G., Hauri, H. P., Simons, K. & Zerial, M. Localization of low molecular weight GTP binding proteins to exocytic and endocytic compartments. Cell 62, 317–329 (1990).

    Article  CAS  PubMed  Google Scholar 

  107. Vieira, O. V. et al. Modulation of Rab5 and Rab7 recruitment to phagosomes by phosphatidylinositol 3-kinase. Mol. Cell Biol. 23, 2501–2514 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Flannagan, R. S., Jaumouille, V. & Grinstein, S. The cell biology of phagocytosis. Annu. Rev. Pathol. 7, 61–98 (2012).

    Article  CAS  PubMed  Google Scholar 

  109. Rubino, M., Miaczynska, M., Lippe, R. & Zerial, M. Selective membrane recruitment of EEA1 suggests a role in directional transport of clathrin-coated vesicles to early endosomes. J. Biol. Chem. 275, 3745–3748 (2000).

    Article  CAS  PubMed  Google Scholar 

  110. Vieira, O. V. et al. Distinct roles of class I and class III phosphatidylinositol 3-kinases in phagosome formation and maturation. J. Cell Biol. 155, 19–25 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Murray, J. T., Panaretou, C., Stenmark, H., Miaczynska, M. & Backer, J. M. Role of Rab5 in the recruitment of hVps34/p150 to the early endosome. Traffic 3, 416–427 (2002).

    Article  CAS  PubMed  Google Scholar 

  112. Kissing, S. et al. Vacuolar ATPase in phagosome-lysosome fusion. J. Biol. Chem. 290, 14166–14180 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Lukacs, G. L., Rotstein, O. D. & Grinstein, S. Determinants of the phagosomal pH in macrophages. In situ assessment of vacuolar H+-ATPase activity, counterion conductance, and H+ “leak”. J. Biol. Chem. 266, 24540–24548 (1991).

    Article  CAS  PubMed  Google Scholar 

  114. Harrison, R. E., Bucci, C., Vieira, O. V., Schroer, T. A. & Grinstein, S. Phagosomes fuse with late endosomes and/or lysosomes by extension of membrane protrusions along microtubules: role of Rab7 and RILP. Mol. Cell Biol. 23, 6494–6506 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Huynh, K. K. et al. LAMP proteins are required for fusion of lysosomes with phagosomes. EMBO J. 26, 313–324 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Braun, V. et al. TI-VAMP/VAMP7 is required for optimal phagocytosis of opsonised particles in macrophages. EMBO J. 23, 4166–4176 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Fairn, G. D. & Grinstein, S. How nascent phagosomes mature to become phagolysosomes. Trends Immunol. 33, 397–405 (2012).

    Article  CAS  PubMed  Google Scholar 

  118. Collins, R. F., Schreiber, A. D., Grinstein, S. & Trimble, W. S. Syntaxins 13 and 7 function at distinct steps during phagocytosis. J. Immunol. 169, 3250–3256 (2002).

    Article  CAS  PubMed  Google Scholar 

  119. Xu, H. & Ren, D. Lysosomal physiology. Annu. Rev. Physiol. 77, 57–80 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Martinez, J. et al. Microtubule-associated protein 1 light chain 3 alpha (LC3)-associated phagocytosis is required for the efficient clearance of dead cells. Proc. Natl Acad. Sci. USA 108, 17396–17401 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Martinez, J. et al. Molecular characterization of LC3-associated phagocytosis reveals distinct roles for rubicon, NOX2 and autophagy proteins. Nat. Cell Biol. 17, 893–906 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Wong, S. W., Sil, P. & Martinez, J. Rubicon: LC3-associated phagocytosis and beyond. FEBS J. 285, 1379–1388 (2018).

    Article  CAS  PubMed  Google Scholar 

  123. Heckmann, B. L., Boada-Romero, E., Cunha, L. D., Magne, J. & Green, D. R. LC3-associated phagocytosis and inflammation. J. Mol. Biol. 429, 3561–3576 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Heckmann, B. L. & Green, D. R. LC3-associated phagocytosis at a glance. J. Cell Sci. 132, 222984 (2019).

    Article  CAS  Google Scholar 

  125. Martinez, J. et al. Noncanonical autophagy inhibits the autoinflammatory, lupus-like response to dying cells. Nature 533, 115–119 (2016). A demonstration that genetic ablation of LAP in myeloid cells promotes spontaneous lupus-like disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Heckmann, B. L. et al. LC3-associated endocytosis facilitates beta-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s disease. Cell, 536–551.e14 (2019).

  127. Nakamura, S. & Yoshimori, T. New insights into autophagosome-lysosome fusion. J. Cell Sci. 130, 1209–1216 (2017).

    CAS  PubMed  Google Scholar 

  128. Pankiv, S. et al. FYCO1 is a Rab7 effector that binds to LC3 and PI3P to mediate microtubule plus end-directed vesicle transport. J. Cell Biol. 188, 253–269 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. McEwan, D. G. et al. PLEKHM1 regulates autophagosome-lysosome fusion through HOPS complex and LC3/GABARAP proteins. Mol. Cell 57, 39–54 (2015).

    Article  CAS  PubMed  Google Scholar 

  130. Tabata, K. et al. Rubicon and PLEKHM1 negatively regulate the endocytic/autophagic pathway via a novel Rab7-binding domain. Mol. Biol. Cell 21, 4162–4172 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Heckmann, B. L. et al. Liver X receptor alpha mediates hepatic triglyceride accumulation through upregulation of G0/G1 switch gene 2 expression. JCI Insight 2, e88735 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Kidani, Y. & Bensinger, S. J. Liver X receptor and peroxisome proliferator-activated receptor as integrators of lipid homeostasis and immunity. Immunol. Rev. 249, 72–83 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Schulman, I. G. Liver X receptors link lipid metabolism and inflammation. FEBS Lett. 591, 2978–2991 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Zhang, X., Heckmann, B. L., Campbell, L. E. & Liu, J. G0S2: a small giant controller of lipolysis and adipose-liver fatty acid flux. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 1862, 1146–1154 (2017).

    Article  CAS  PubMed  Google Scholar 

  135. N, A. G. et al. Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR. Immunity 31, 245–258 (2009).

    Article  CAS  Google Scholar 

  136. Rebe, C. et al. Induction of transglutaminase 2 by a liver X receptor/retinoic acid receptor alpha pathway increases the clearance of apoptotic cells by human macrophages. Circ. Res. 105, 393–401 (2009).

    Article  CAS  PubMed  Google Scholar 

  137. Fond, A. M., Lee, C. S., Schulman, I. G., Kiss, R. S. & Ravichandran, K. S. Apoptotic cells trigger a membrane-initiated pathway to increase ABCA1. J. Clin. Invest. 125, 2748–2758 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Kiss, R. S., Elliott, M. R., Ma, Z., Marcel, Y. L. & Ravichandran, K. S. Apoptotic cells induce a phosphatidylserine-dependent homeostatic response from phagocytes. Curr. Biol. 16, 2252–2258 (2006).

    Article  CAS  PubMed  Google Scholar 

  139. Yoon, Y. S. et al. PPARgamma activation following apoptotic cell instillation promotes resolution of lung inflammation and fibrosis via regulation of efferocytosis and proresolving cytokines. Mucosal Immunol. 8, 1031–1046 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Cunha, L. D. et al. LC3-Associated phagocytosis in myeloid cells promotes tumor immune tolerance. Cell 175, 429–441.e16 (2018). Genetic ablation of LAP in myeloid cells of the tumour microenvironment promotes anticancer immunity in several model systems by the engagement of a type I interferon response.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Yokoyama, K. et al. Rab27a negatively regulates phagocytosis by prolongation of the actin-coating stage around phagosomes. J. Biol. Chem. 286, 5375–5382 (2011).

    Article  CAS  PubMed  Google Scholar 

  142. Kuiper, J. W. et al. Creatine kinase-mediated ATP supply fuels actin-based events in phagocytosis. PLoS Biol. 6, e51 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. Lucin, K. M. et al. Microglial beclin 1 regulates retromer trafficking and phagocytosis and is impaired in Alzheimer’s disease. Neuron 79, 873–886 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Baumann, I. et al. Impaired uptake of apoptotic cells into tingible body macrophages in germinal centers of patients with systemic lupus erythematosus. Arthritis Rheum. 46, 191–201 (2002).

    Article  PubMed  Google Scholar 

  145. Liu, Z. & Davidson, A. Taming lupus-a new understanding of pathogenesis is leading to clinical advances. Nat. Med. 18, 871–882 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  146. Berden, J. H. Lupus nephritis. Kidney Int. 52, 538–558 (1997).

    Article  CAS  PubMed  Google Scholar 

  147. van Bruggen, M. C. et al. Antigen specificity of anti-nuclear antibodies complexed to nucleosomes determines glomerular basement membrane binding in vivo. Eur. J. Immunol. 27, 1564–1569 (1997).

    Article  PubMed  Google Scholar 

  148. Witting, A., Muller, P., Herrmann, A., Kettenmann, H. & Nolte, C. Phagocytic clearance of apoptotic neurons by Microglia/Brain macrophages in vitro: involvement of lectin-, integrin-, and phosphatidylserine-mediated recognition. J. Neurochem. 75, 1060–1070 (2000).

    Article  CAS  PubMed  Google Scholar 

  149. Galloway, D. A., Phillips, A. E. M., Owen, D. R. J. & Moore, C. S. Phagocytosis in the brain: homeostasis and disease. Front. Immunol. 10, 790 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Mattson, M. P. Apoptosis in neurodegenerative disorders. Nat. Rev. Mol. Cell Biol. 1, 120–129 (2000).

    Article  CAS  PubMed  Google Scholar 

  151. Heckmann, B. L., Tummers, B. & Green, D. R. Crashing the computer: apoptosis vs. necroptosis in neuroinflammation. Cell Death Differ. 26, 41–52 (2019).

    Article  PubMed  Google Scholar 

  152. Fricker, M. et al. MFG-E8 mediates primary phagocytosis of viable neurons during neuroinflammation. J. Neurosci. 32, 2657–2666 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Fuller, A. D. & Van Eldik, L. J. MFG-E8 regulates microglial phagocytosis of apoptotic neurons. J. Neuroimmune Pharmacol. 3, 246–256 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  154. Ferguson, T. A. & Green, D. R. Autophagy and phagocytosis converge for better vision. Autophagy 10, 165–167 (2014).

    Article  CAS  PubMed  Google Scholar 

  155. Kim, J. Y. et al. Noncanonical autophagy promotes the visual cycle. Cell 154, 365–376 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Nandrot, E. F. & Dufour, E. M. Mertk in daily retinal phagocytosis: a history in the making. Adv. Exp. Med. Biol. 664, 133–140 (2010).

    Article  CAS  PubMed  Google Scholar 

  157. Yang, H. et al. Activation of liver X receptor alleviates ocular inflammation in experimental autoimmune uveitis. Invest. Ophthalmol. Vis. Sci. 55, 2795–2804 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Fox, S., Leitch, A. E., Duffin, R., Haslett, C. & Rossi, A. G. Neutrophil apoptosis: relevance to the innate immune response and inflammatory disease. J. Innate Immun. 2, 216–227 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Juncadella, I. J. et al. Apoptotic cell clearance by bronchial epithelial cells critically influences airway inflammation. Nature 493, 547–551 (2013).

    Article  CAS  PubMed  Google Scholar 

  160. Hodge, S., Hodge, G., Scicchitano, R., Reynolds, P. N. & Holmes, M. Alveolar macrophages from subjects with chronic obstructive pulmonary disease are deficient in their ability to phagocytose apoptotic airway epithelial cells. Immunol. Cell Biol. 81, 289–296 (2003).

    Article  PubMed  Google Scholar 

  161. Vandivier, R. W. et al. Impaired clearance of apoptotic cells from cystic fibrosis airways. Chest 121, 89S (2002).

    Article  PubMed  Google Scholar 

  162. Ley, K., Miller, Y. I. & Hedrick, C. C. Monocyte and macrophage dynamics during atherogenesis. Arterioscler. Thromb. Vasc. Biol. 31, 1506–1516 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Tabas, I. Consequences and therapeutic implications of macrophage apoptosis in atherosclerosis: the importance of lesion stage and phagocytic efficiency. Arterioscler. Thromb. Vasc. Biol. 25, 2255–2264 (2005).

    Article  CAS  PubMed  Google Scholar 

  164. Poon, I. K., Lucas, C. D., Rossi, A. G. & Ravichandran, K. S. Apoptotic cell clearance: basic biology and therapeutic potential. Nat. Rev. Immunol. 14, 166–180 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Schrijvers, D. M., De Meyer, G. R., Kockx, M. M., Herman, A. G. & Martinet, W. Phagocytosis of apoptotic cells by macrophages is impaired in atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 25, 1256–1261 (2005).

    Article  CAS  PubMed  Google Scholar 

  166. Vucic, E. et al. Regression of inflammation in atherosclerosis by the LXR agonist R211945: a noninvasive assessment and comparison with atorvastatin. JACC Cardiovasc. Imaging 5, 819–828 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  167. Li, B. Z., Zhang, H. Y., Pan, H. F. & Ye, D. Q. Identification of MFG-E8 as a novel therapeutic target for diseases. Expert Opin. Ther. Targets 17, 1275–1285 (2013).

    Article  CAS  PubMed  Google Scholar 

  168. Cuchel, M. & Rader, D. J. Macrophage reverse cholesterol transport: key to the regression of atherosclerosis? Circulation 113, 2548–2555 (2006).

    Article  PubMed  Google Scholar 

  169. Oram, J. F. & Heinecke, J. W. ATP-binding cassette transporter A1: a cell cholesterol exporter that protects against cardiovascular disease. Physiol. Rev. 85, 1343–1372 (2005).

    Article  CAS  PubMed  Google Scholar 

  170. Tang, C. & Oram, J. F. The cell cholesterol exporter ABCA1 as a protector from cardiovascular disease and diabetes. Biochim. Biophys. Acta 1791, 563–572 (2009).

    Article  CAS  PubMed  Google Scholar 

  171. Zhu, X. et al. Macrophage ABCA1 reduces MyD88-dependent Toll-like receptor trafficking to lipid rafts by reduction of lipid raft cholesterol. J. Lipid Res. 51, 3196–3206 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Loirand, G., Guerin, P. & Pacaud, P. Rho kinases in cardiovascular physiology and pathophysiology. Circ. Res. 98, 322–334 (2006).

    Article  CAS  PubMed  Google Scholar 

  173. Liao, X. et al. Macrophage autophagy plays a protective role in advanced atherosclerosis. Cell Metab. 15, 545–553 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Razani, B. et al. Autophagy links inflammasomes to atherosclerotic progression. Cell Metab. 15, 534–544 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Davies, S. P., Reynolds, G. M. & Stamataki, Z. Clearance of apoptotic cells by tissue epithelia: a putative role for hepatocytes in liver efferocytosis. Front. Immunol. 9, 44 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  176. Llacuna, L. et al. Growth arrest-specific protein 6 is hepatoprotective against murine ischemia/reperfusion injury. Hepatology 52, 1371–1379 (2010).

    Article  CAS  PubMed  Google Scholar 

  177. Vives-Pi, M., Rodriguez-Fernandez, S. & Pujol-Autonell, I. How apoptotic beta-cells direct immune response to tolerance or to autoimmune diabetes: a review. Apoptosis 20, 263–272 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. O’Brien, B. A. et al. A deficiency in the in vivo clearance of apoptotic cells is a feature of the NOD mouse. J. Autoimmun. 26, 104–115 (2006).

    Article  PubMed  CAS  Google Scholar 

  179. Khalifeh-Soltani, A. et al. Mfge8 promotes obesity by mediating the uptake of dietary fats and serum fatty acids. Nat. Med. 20, 175–183 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Khanna, S. et al. Macrophage dysfunction impairs resolution of inflammation in the wounds of diabetic mice. PLoS One 5, e9539 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  181. Maruyama, K. et al. Decreased macrophage number and activation lead to reduced lymphatic vessel formation and contribute to impaired diabetic wound healing. Am. J. Pathol. 170, 1178–1191 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  182. Bossi, F. et al. C1q as a unique player in angiogenesis with therapeutic implication in wound healing. Proc. Natl Acad. Sci. USA 111, 4209–4214 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Bosurgi, L. et al. Macrophage function in tissue repair and remodeling requires IL-4 or IL-13 with apoptotic cells. Science 356, 1072–1076 (2017). While the cytokines IL-4 and IL-13 are involved in the repair of tissue damage during helminth infections, this article shows that efferocytosis of apoptotic cells by macrophages is also required for the repair response.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Weavers, H., Evans, I. R., Martin, P. & Wood, W. Corpse engulfment generates a molecular memory that primes the macrophage inflammatory response. Cell 165, 1658–1671 (2016). In a Drosophila model of tissue damage, efferocytosis of apoptotic cells is required to prime the participation of macrophages in tissue repair.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Beccafico, S. et al. Human muscle satellite cells show age-related differential expression of S100B protein and RAGE. Age 33, 523–541 (2011).

    Article  CAS  PubMed  Google Scholar 

  186. Zhang, S. et al. Efferocytosis fuels requirements of fatty acid oxidation and the electron transport chain to polarize macrophages for tissue repair. Cell Metab. 29, 443–456.e5 (2019). During wound injury, clearance of dying cells fills the phagocytic cell with a metabolite load nearly equal to that at rest. Here, the authors investigate how metabolic phagocytic signalling regulates the signature anti-inflammatory macrophage response.

    Article  CAS  PubMed  Google Scholar 

  187. Kawane, K. et al. Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages. Nature 443, 998–1002 (2006).

    Article  CAS  PubMed  Google Scholar 

  188. Park, M. C., Kwon, Y. J., Chung, S. J., Park, Y. B. & Lee, S. K. Liver X receptor agonist prevents the evolution of collagen-induced arthritis in mice. Rheumatology 49, 882–890 (2010).

    Article  CAS  PubMed  Google Scholar 

  189. Elliott, M. R. & Ravichandran, K. S. ELMO1 signaling in apoptotic germ cell clearance and spermatogenesis. Ann. NY Acad. Sci. 1209, 30–36 (2010).

    Article  CAS  PubMed  Google Scholar 

  190. Burnier, L. et al. Gas6 deficiency in recipient mice of allogeneic transplantation alleviates hepatic graft-versus-host disease. Blood 115, 3390–3397 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Yan, X. et al. Annexin-V promotes anti-tumor immunity and inhibits neuroblastoma growth in vivo. Cancer Immunol. Immunother. 61, 1917–1927 (2012).

    Article  CAS  PubMed  Google Scholar 

  192. Stach, C. M. et al. Treatment with annexin V increases immunogenicity of apoptotic human T-cells in Balb/c mice. Cell Death Differ. 7, 911–915 (2000).

    Article  CAS  PubMed  Google Scholar 

  193. Schlegel, J. et al. MERTK receptor tyrosine kinase is a therapeutic target in melanoma. J. Clin. Invest. 123, 2257–2267 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Suresh, K. et al. CD36 mediates H2O2-induced calcium influx in lung microvascular endothelial cells. Am. J. Physiol. Lung Cell Mol. Physiol. 312, L143–L153 (2017). Genetic loss or pharmacologic inhibition of CD36 attenuates the damage induced by hydrogen peroxide in the lung and protects from ischaemia–reperfusion injury.

    Article  PubMed  Google Scholar 

  195. Segawa, K. et al. Caspase-mediated cleavage of phospholipid flippase for apoptotic phosphatidylserine exposure. Science 344, 1164–1168 (2014).

    Article  CAS  PubMed  Google Scholar 

  196. Li, H., Zhu, H., Xu, C. J. & Yuan, J. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94, 491–501 (1998).

    Article  CAS  PubMed  Google Scholar 

  197. Weinlich, R., Oberst, A., Beere, H. M. & Green, D. R. Necroptosis in development, inflammation and disease. Nat. Rev. Mol. Cell Biol. 18, 127–136 (2017).

    Article  CAS  PubMed  Google Scholar 

  198. Tummers, B. & Green, D. R. Caspase-8: regulating life and death. Immunol. Rev. 277, 76–89 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Ingram, J. P. et al. ZBP1/DAI drives RIPK3-mediated cell death induced by IFNs in the absence of RIPK1. J. Immunol. 203, 1348–1355 (2019).

    Article  CAS  PubMed  Google Scholar 

  200. Kaiser, W. J. et al. Toll-like receptor 3-mediated necrosis via TRIF, RIP3, and MLKL. J. Biol. Chem. 288, 31268–31279 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Man, S. M., Karki, R. & Kanneganti, T. D. Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases. Immunol. Rev. 277, 61–75 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Kayagaki, N. et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 526, 666–671 (2015). Caspase 11 cleavage of gasdermin D is responsible for pyroptotic activation, IL-1 processing and septic shock following infection with Gram-negative bacteria.

    Article  CAS  PubMed  Google Scholar 

  203. Shi, J. et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526, 660–665 (2015). Identification of gasdermin D as a regulator of pyroptosis downstream of inflammatory caspase activation.

    Article  CAS  PubMed  Google Scholar 

  204. Ding, J. et al. Pore-forming activity and structural autoinhibition of the gasdermin family. Nature 535, 111–116 (2016).

    Article  CAS  PubMed  Google Scholar 

  205. Doll, S. et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat. Chem. Biol. 13, 91–98 (2017). ACSL4 enriches cellular membranes with long polyunsaturated fatty acids required for ferroptosis.

    Article  CAS  PubMed  Google Scholar 

  206. Kagan, V. E. et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat. Chem. Biol. 13, 81–90 (2017). Discovery of a highly organized oxygenation centre leading to oxidation of specific phospholipid species that direct cells towards ferroptosis.

    Article  CAS  PubMed  Google Scholar 

  207. Rider, P., Voronov, E., Dinarello, C. A., Apte, R. N. & Cohen, I. Alarmins: feel the stress. J. Immunol. 198, 1395–1402 (2017).

    Article  CAS  PubMed  Google Scholar 

  208. Roh, J. S. & Sohn, D. H. Damage-associated molecular patterns in inflammatory diseases. Immune Netw. 18, e27 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  209. Gong, T., Liu, L., Jiang, W. & Zhou, R. DAMP-sensing receptors in sterile inflammation and inflammatory diseases. Nat. Rev. Immunol. 20, 95–112 (2020).

    Article  CAS  PubMed  Google Scholar 

  210. Yu, X., Feng, B., He, P. & Shan, L. From chaos to harmony: responses and signaling upon microbial pattern recognition. Annu. Rev. Phytopathol. 55, 109–137 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Brubaker, S. W., Bonham, K. S., Zanoni, I. & Kagan, J. C. Innate immune pattern recognition: a cell biological perspective. Annu. Rev. Immunol. 33, 257–290 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Rubartelli, A. & Lotze, M. T. Inside, outside, upside down: damage-associated molecular-pattern molecules (DAMPs) and redox. Trends Immunol. 28, 429–436 (2007).

    Article  CAS  PubMed  Google Scholar 

  213. Broz, P. & Monack, D. M. Newly described pattern recognition receptors team up against intracellular pathogens. Nat. Rev. Immunol. 13, 551–565 (2013).

    Article  CAS  PubMed  Google Scholar 

  214. Tang, D., Kang, R., Coyne, C. B., Zeh, H. J. & Lotze, M. T. PAMPs and DAMPs: signal 0 s that spur autophagy and immunity. Immunol. Rev. 249, 158–175 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Mogensen, T. H. Pathogen recognition and inflammatory signaling in innate immune defenses. Clin. Microbiol. Rev. 22, 240–273 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Takeuchi, O. & Akira, S. Pattern recognition receptors and inflammation. Cell 140, 805–820 (2010).

    Article  CAS  PubMed  Google Scholar 

  217. Le, L. Q. et al. Mice lacking the orphan G protein-coupled receptor G2A develop a late-onset autoimmune syndrome. Immunity 14, 561–571 (2001).

    Article  CAS  PubMed  Google Scholar 

  218. Mike, E. V. et al. Neuropsychiatric systemic lupus erythematosus is dependent on sphingosine-1-phosphate signaling. Front. Immunol. 9, 2189 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  219. Miyanishi, M., Segawa, K. & Nagata, S. Synergistic effect of Tim4 and MFG-E8 null mutations on the development of autoimmunity. Int. Immunol. 24, 551–559 (2012).

    Article  CAS  PubMed  Google Scholar 

  220. Potter, P. K., Cortes-Hernandez, J., Quartier, P., Botto, M. & Walport, M. J. Lupus-prone mice have an abnormal response to thioglycolate and an impaired clearance of apoptotic cells. J. Immunol. 170, 3223–3232 (2003).

    Article  CAS  PubMed  Google Scholar 

  221. van Zoelen, M. A. & van der Poll, T. Targeting RAGE in sepsis. Crit. Care 12, 103 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  222. Tian, L. et al. p85alpha recruitment by the CD300f phosphatidylserine receptor mediates apoptotic cell clearance required for autoimmunity suppression. Nat. Commun. 5, 3146 (2014).

    Article  PubMed  CAS  Google Scholar 

  223. Schittenhelm, L., Hilkens, C. M. & Morrison, V. L. beta2 integrins as regulators of dendritic cell, monocyte, and macrophage function. Front. Immunol. 8, 1866 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  224. Hanayama, R., Miyasaka, K., Nakaya, M. & Nagata, S. MFG-E8-dependent clearance of apoptotic cells, and autoimmunity caused by its failure. Curr. Dir. Autoimmun. 9, 162–172 (2006).

    CAS  PubMed  Google Scholar 

  225. Kruse, K. et al. Inefficient clearance of dying cells in patients with SLE: anti-dsDNA autoantibodies, MFG-E8, HMGB-1 and other players. Apoptosis 15, 1098–1113 (2010).

    Article  CAS  PubMed  Google Scholar 

  226. Cohen, P. L. & Shao, W. H. Gas6/TAM receptors in systemic lupus erythematosus. Dis. Markers 2019, 7838195 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  227. ten Kate, M. K. & van der Meer, J. Protein S deficiency: a clinical perspective. Haemophilia 14, 1222–1228 (2008).

    PubMed  Google Scholar 

  228. Ramirez-Ortiz, Z. G. et al. The scavenger receptor SCARF1 mediates the clearance of apoptotic cells and prevents autoimmunity. Nat. Immunol. 14, 917–926 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Walport, M. J., Davies, K. A. & Botto, M. C1q and systemic lupus erythematosus. Immunobiology 199, 265–285 (1998).

    Article  CAS  PubMed  Google Scholar 

  230. Zeng, T. et al. The detection of autoantibodies to ATP-binding cassette transporter A1 and its role in the pathogenesis of atherosclerosis in patients with systemic lupus erythematosus. Clin. Biochem. 45, 1342–1346 (2012).

    Article  CAS  PubMed  Google Scholar 

  231. Lutz, S. E. et al. Contribution of pannexin1 to experimental autoimmune encephalomyelitis. PLoS One 8, e66657 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Duman, J. G., Tu, Y. K. & Tolias, K. F. Emerging roles of BAI adhesion-GPCRs in synapse development and plasticity. Neural Plast. 2016, 8301737 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  233. Wium, M., Paccez, J. D. & Zerbini, L. F. The dual role of TAM receptors in autoimmune diseases and cancer: an overview. Cells 7, 166 (2018).

    Article  CAS  PubMed Central  Google Scholar 

  234. Binder, M. D. et al. Gas6 deficiency increases oligodendrocyte loss and microglial activation in response to cuprizone-induced demyelination. J. Neurosci. 28, 5195–5206 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Chu, Y. et al. Enhanced synaptic connectivity and epilepsy in C1q knockout mice. Proc. Natl Acad. Sci. USA 107, 7975–7980 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Chen, X. et al. Apoptotic engulfment pathway and schizophrenia. PLoS One 4, e6875 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  237. Li, Z. & Weinman, S. A. Regulation of hepatic inflammation via macrophage cell death. Semin. Liver Dis. 38, 340–350 (2018).

    Article  CAS  PubMed  Google Scholar 

  238. Bellan, M. et al. Gas6/TAM system: a key modulator of the interplay between inflammation and fibrosis. Int. J. Mol. Sci. 20, 5070 (2019).

    Article  CAS  PubMed Central  Google Scholar 

  239. Elliott, M. R. et al. Unexpected requirement for ELMO1 in clearance of apoptotic germ cells in vivo. Nature 467, 333–337 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Cattaneo, M. The platelet P2 receptors in inflammation. Hamostaseologie 35, 262–266 (2015).

    Article  CAS  PubMed  Google Scholar 

  241. Henson, P. M. & Bratton, D. L. Allergy: airway epithelial Rac1 suppresses allergic inflammation. Curr. Biol. 23, R104–R106 (2013).

    Article  CAS  PubMed  Google Scholar 

  242. Good, M. E. et al. Pannexin 1 channels as an unexpected new target of the anti-hypertensive drug spironolactone. Circ. Res. 122, 606–615 (2018).

    Article  CAS  PubMed  Google Scholar 

  243. Liu, H. & Jiang, D. Fractalkine/CX3CR1 and atherosclerosis. Clin. Chim. Acta 412, 1180–1186 (2011).

    Article  CAS  PubMed  Google Scholar 

  244. Liu, M., Tso, P. & Woods, S. C. Receptor CD36 links a risk-associated allele to obesity and metabolic disorders. J. Biol. Chem. 293, 13349–13350 (2018). Pharmacologic inhibition of integral membrane protein CD36 significantly reduces body weight gain and improves glucose tolerance in animals receiving a high-fat diet.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Boucher, P. & Herz, J. Signaling through LRP1: protection from atherosclerosis and beyond. Biochem. Pharmacol. 81, 1–5 (2011).

    Article  CAS  PubMed  Google Scholar 

  246. Bhatia, V. K. et al. Complement C1q reduces early atherosclerosis in low-density lipoprotein receptor-deficient mice. Am. J. Pathol. 170, 416–426 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  247. Freemerman, A. J. et al. Myeloid Slc2a1-deficient murine model revealed macrophage activation and metabolic phenotype are fueled by GLUT1. J. Immunol. 202, 1265–1286 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Thorp, E. B. Mechanisms of failed apoptotic cell clearance by phagocyte subsets in cardiovascular disease. Apoptosis 15, 1124–1136 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  249. Qi, Y. Y., Zhou, X. J. & Zhang, H. Autophagy and immunological aberrations in systemic lupus erythematosus. Eur. J. Immunol. 49, 523–533 (2019).

    Article  CAS  PubMed  Google Scholar 

  250. Duval, C., Chinetti, G., Trottein, F., Fruchart, J. C. & Staels, B. The role of PPARs in atherosclerosis. Trends Mol. Med. 8, 422–430 (2002).

    Article  CAS  PubMed  Google Scholar 

  251. Rogers, M. A. et al. Dynamin-related protein 1 inhibition attenuates cardiovascular calcification in the presence of oxidative stress. Circ. Res. 121, 220–233 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. Schledzewski, K. et al. Deficiency of liver sinusoidal scavenger receptors stabilin-1 and -2 in mice causes glomerulofibrotic nephropathy via impaired hepatic clearance of noxious blood factors. J. Clin. Invest. 121, 703–714 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  253. Frasch, S. C. et al. G2A signaling dampens colitic inflammation via production of IFN-gamma. J. Immunol. 197, 1425–1434 (2016).

    Article  CAS  PubMed  Google Scholar 

  254. Huveneers, S., Truong, H. & Danen, H. J. Integrins: signaling, disease, and therapy. Int. J. Radiat. Biol. 83, 743–751 (2007).

    Article  CAS  PubMed  Google Scholar 

  255. Marei, H. & Malliri, A. Rac1 in human diseases: the therapeutic potential of targeting Rac1 signaling regulatory mechanisms. Small GTPases 8, 139–163 (2017).

    Article  CAS  PubMed  Google Scholar 

  256. Riuzzi, F. et al. RAGE in the pathophysiology of skeletal muscle. J. Cachexia Sarcopenia Muscle 9, 1213–1234 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  257. Wu, G. et al. Molecular insights of Gas6/TAM in cancer development and therapy. Cell Death Dis. 8, e2700 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the US National Institutes of Health (AI40646 and CA231620 to D.R.G.; AI138492 and CA231423 to B.L.H.), American Lebanese Syrian Associated Charities and the John H. Sununu Endowed Fellowship to B.L.H. and an EMBO Long-Term Fellowship (ALTF 1526 -2016) to E.B.R.

Author information

Authors and Affiliations

Authors

Contributions

The authors contributed equally to all aspects of the article.

Corresponding authors

Correspondence to Bradlee L. Heckmann or Douglas R. Green.

Ethics declarations

Competing interests

D.R.G. is on the scientific advisory board of Inzen. The other authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Molecular Cell Biology thanks Edward Thorp, Martin Herrman and the other, anonymous, reviewer for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Efferocytosis

Engulfment and clearance of dead and dying cells, usually (although not exclusively) by myeloid cells such as macrophages.

Entosis

A process by which a living cell invades or is engulfed by another. This process differs from the clearance of apoptotic cells by phagocytosis as the internalized cell is still alive.

Inflammasome

Any molecular complex capable of activating caspase 1.

Immune tolerance

Lack or inhibition of an adaptive immune response to specific antigens.

Flippase

A membrane protein that transports phosphatidylserine from the outer leaflet to the inner leaflet of the plasma membrane.

Scramblase

A membrane protein that, on activation, equilibrates (‘scrambles’) the distribution of phospholipids between the inner and outer leaflets of the plasma membrane.

MLKL

Mixed-lineage kinase domain-like protein (MLKL) is the executioner in necroptosis, disrupting the plasma membrane following its phosphorylation.

Gasdermins

Proteins that, on activation, create pores in the plasma membrane; gasdermin D and gasdermin E function in pyroptosis.

Guanine nucleotide exchange factor

(GEF). An enzyme that activates monomeric GTPases, including RAS, RAC and RHO. GEFs stimulate the release of GDP to allow binding of GTP.

Dynamin

A member of the protein GTPase family, mainly involved in the scission of newly formed vesicles from a membrane and their fusion with another membrane.

Microtubule-associated protein 1A/1B light chain 3 (LC3)-associated phagocytosis

(LAP). A non-apoptotic function of several proteins of the autophagy pathway, resulting in lipidation of LC3 family proteins on the phagosome membrane, enhancing fusion of the phagosome with lysosomes.

SNARE complex

Soluble N-ethylmaleimide-sensitive fusion protein attachment protein (SNAP) receptor complex involved in fusion of the vesicular membrane to other membranes.

Phagolysosome

The intracellular vesicle that results from the fusion of the phagosome with lysosomes.

Cathepsins

A class of proteases mostly present in lysosomes.

LC3 family

The ATG8 protein family, including microtubule-associated protein 1A/1B light chain 3 (LC3) proteins, γ-aminobutyric acid receptor-associated protein (GABARAP), GEC1 and GATE-16.

Chromophore

A substance or molecule that absorbs light, critical for animal and human vision (for example, retinal).

Langerhans cells

Specialized dendritic cells residing in the epidermis of the skin.

Graft-versus-host disease

Disease resulting from the introduction and action of allogeneic T lymphocytes, which can occur following transplant of bone marrow from which T cells have not been removed.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Boada-Romero, E., Martinez, J., Heckmann, B.L. et al. The clearance of dead cells by efferocytosis. Nat Rev Mol Cell Biol 21, 398–414 (2020). https://doi.org/10.1038/s41580-020-0232-1

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41580-020-0232-1

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing