Tissue macrophages rapidly recognize and engulf apoptotic cells. These events require the display of so-called eat-me signals on the apoptotic cell surface, the most fundamental of which is phosphatidylserine (PtdSer). Externalization of this phospholipid is catalysed by scramblase enzymes, several of which are activated by caspase cleavage. PtdSer is detected both by macrophage receptors that bind to this phospholipid directly and by receptors that bind to a soluble bridging protein that is independently bound to PtdSer. Prominent among the latter receptors are the MER and AXL receptor tyrosine kinases. Eat-me signals also trigger macrophages to engulf virus-infected or metabolically traumatized, but still living, cells, and this ‘murder by phagocytosis’ may be a common phenomenon. Finally, the localized presentation of PtdSer and other eat-me signals on delimited cell surface domains may enable the phagocytic pruning of these ‘locally dead’ domains by macrophages, most notably by microglia of the central nervous system.
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Nagata, S. Apoptosis and clearance of apoptotic cells. Annu. Rev. Immunol. 36, 489–517 (2018).
Elliott, M. R. & Ravichandran, K. S. The dynamics of apoptotic cell clearance. Dev. Cell 38, 147–160 (2016).
Gordon, S. & Pluddemann, A. Macrophage clearance of apoptotic cells: a critical assessment. Front. Immunol. 9, 127 (2018).
Epelman, S., Lavine, K. J. & Randolph, G. J. Origin and functions of tissue macrophages. Immunity 41, 21–35 (2014).
Krysko, D. V., Vanden Berghe, T., D’Herde, K. & Vandenabeele, P. Apoptosis and necrosis: detection, discrimination and phagocytosis. Methods 44, 205–221 (2008).
deCathelineau, A. M. & Henson, P. M. The final step in programmed cell death: phagocytes carry apoptotic cells to the grave. Essays Biochem. 39, 105–117 (2003).
Surh, C. D. & Sprent, J. T cell apoptosis detected in situ during positive and negative selection in the thymus. Nature 372, 100–103 (1994).
Earnshaw, W. C., Martins, L. M. & Kaufmann, S. H. Mammalian caspases: structure, activation, substrates, and functions during apoptosis. Annu. Rev. Biochem. 68, 383–424 (1999).
Mahajan, A., Herrmann, M. & Munoz, L. E. Clearance deficiency and cell death pathways: a model for the pathogenesis of SLE. Front. Immunol. 7, 35 (2016).
Abdolmaleki, F. et al. The role of efferocytosis in autoimmune diseases. Front. Immunol. 9, 1645 (2018).
Fourgeaud, L. et al. TAM receptors regulate multiple features of microglial physiology. Nature 532, 240–244 (2016). This paper highlights a role for microglial MER in the steady state phagocytosis of apoptotic cells in the neurogenic regions of the adult brain.
Sierra, A. et al. Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell 7, 483–495 (2010).
McGaha, T. L. & Karlsson, M. C. Apoptotic cell responses in the splenic marginal zone: a paradigm for immunologic reactions to apoptotic antigens with implications for autoimmunity. Immunol. Rev. 269, 26–43 (2016).
Peter, C., Wesselborg, S., Herrmann, M. & Lauber, K. Dangerous attraction: phagocyte recruitment and danger signals of apoptotic and necrotic cells. Apoptosis 15, 1007–1028 (2010).
Medina, C. B. & Ravichandran, K. S. Do not let death do us part: ‘find-me’ signals in communication between dying cells and the phagocytes. Cell Death Differ. 23, 979–989 (2016).
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).
Peter, C. et al. Migration to apoptotic “find-me” signals is mediated via the phagocyte receptor G2A. J. Biol. Chem. 283, 5296–5305 (2008).
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).
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).
Peter, C. et al. Release of lysophospholipid ‘find-me’ signals during apoptosis requires the ATP-binding cassette transporter A1. Autoimmunity 45, 568–573 (2012).
Wu, Y. C. & Horvitz, H. R. The C. elegans cell corpse engulfment gene ced-7 encodes a protein similar to ABC transporters. Cell 93, 951–960 (1998).
Chekeni, F. B. et al. Pannexin 1 channels mediate ‘find-me’ signal release and membrane permeability during apoptosis. Nature 467, 863–867 (2010).
Sandilos, J. K. et al. Pannexin 1, an ATP release channel, is activated by caspase cleavage of its pore-associated C-terminal autoinhibitory region. J. Biol. Chem. 287, 11303–11311 (2012).
Sandilos, J. K. & Bayliss, D. A. Physiological mechanisms for the modulation of pannexin 1 channel activity. J. Physiol. 590, 6257–6266 (2012).
Chiu, Y. H. et al. A quantized mechanism for activation of pannexin channels. Nat. Commun. 8, 14324 (2017).
Truman, L. A. et al. CX3CL1/fractalkine is released from apoptotic lymphocytes to stimulate macrophage chemotaxis. Blood 112, 5026–5036 (2008).
Yang, L. V., Radu, C. G., Wang, L., Riedinger, M. & Witte, O. N. Gi-independent macrophage chemotaxis to lysophosphatidylcholine via the immunoregulatory GPCR G2A. Blood 105, 1127–1134 (2005).
Luo, B. et al. Erythropoeitin signaling in macrophages promotes dying cell clearance and immune tolerance. Immunity 44, 287–302 (2016).
Idzko, M., Ferrari, D. & Eltzschig, H. K. Nucleotide signalling during inflammation. Nature 509, 310–317 (2014).
Haynes, S. E. et al. The P2Y12 receptor regulates microglial activation by extracellular nucleotides. Nat. Neurosci. 9, 1512–1519 (2006).
Gautier, E. L. et al. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat. Immunol. 13, 1118–1128 (2012).
ImmGen, C. Open-source ImmGen: mononuclear phagocytes. Nat. Immunol. 17, 741 (2016).
Ohsawa, K. et al. P2Y12 receptor-mediated integrin-beta1 activation regulates microglial process extension induced by ATP. Glia 58, 790–801 (2010).
Zrzavy, T. et al. Loss of ‘homeostatic’ microglia and patterns of their activation in active multiple sclerosis. Brain 140, 1900–1913 (2017).
Kronlage, M. et al. Autocrine purinergic receptor signaling is essential for macrophage chemotaxis. Sci. Signal. 3, ra55 (2010).
Fadok, V. A. et al. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J. Immunol. 148, 2207–2216 (1992). This paper identifies externalized PtdSer as an eat-me signal for phagocytosis of apoptotic cells.
Birge, R. B. et al. Phosphatidylserine is a global immunosuppressive signal in efferocytosis, infectious disease, and cancer. Cell Death Differ. 23, 962–978 (2016).
Leventis, P. A. & Grinstein, S. The distribution and function of phosphatidylserine in cellular membranes. Annu. Rev. Biophys. 39, 407–427 (2010).
van Meer, G. Dynamic transbilayer lipid asymmetry. Cold Spring Harb. Perspect. Biol. 3, a004671 (2011).
Andersen, J. P. et al. P4-ATPases as phospholipid flippases-structure, function, and enigmas. Front. Physiol. 7, 275 (2016).
Shin, H. W. & Takatsu, H. Substrates of P4-ATPases: beyond aminophospholipids (phosphatidylserine and phosphatidylethanolamine). FASEB J. 33, 3087–3096 (2018).
Nagata, S., Suzuki, J., Segawa, K. & Fujii, T. Exposure of phosphatidylserine on the cell surface. Cell Death Differ. 23, 952–961 (2016).
Pomorski, T. G. & Menon, A. K. Lipid somersaults: uncovering the mechanisms of protein-mediated lipid flipping. Prog. Lipid Res. 64, 69–84 (2016).
Tang, X., Halleck, M. S., Schlegel, R. A. & Williamson, P. A subfamily of P-type ATPases with aminophospholipid transporting activity. Science 272, 1495–1497 (1996).
Segawa, K., Kurata, S. & Nagata, S. Human type IV P-type ATPases that work as plasma membrane phospholipid flippases and their regulation by caspase and calcium. J. Biol. Chem. 291, 762–772 (2016).
Segawa, K. et al. Caspase-mediated cleavage of phospholipid flippase for apoptotic phosphatidylserine exposure. Science 344, 1164–1168 (2014). This paper identifies ATP11C as a PtdSer flippase whose enzymatic activity is lost upon caspase cleavage.
Segawa, K. et al. Phospholipid flippases enable precursor B cells to flee engulfment by macrophages. Proc. Natl Acad. Sci. USA 115, 12212–12217 (2018).
Coleman, J. A. & Molday, R. S. Critical role of the beta-subunit CDC50A in the stable expression, assembly, subcellular localization, and lipid transport activity of the P4-ATPase ATP8A2. J. Biol. Chem. 286, 17205–17216 (2011).
Kornberg, R. D. & McConnell, H. M. Inside-outside transitions of phospholipids in vesicle membranes. Biochemistry 10, 1111–1120 (1971).
Whitlock, J. M. & Hartzell, H. C. Anoctamins/TMEM16 proteins: chloride channels flirting with lipids and extracellular vesicles. Annu. Rev. Physiol. 79, 119–143 (2017).
Suzuki, J. et al. Calcium-dependent phospholipid scramblase activity of TMEM16 protein family members. J. Biol. Chem. 288, 13305–13316 (2013).
Suzuki, J., Imanishi, E. & Nagata, S. Xkr8 phospholipid scrambling complex in apoptotic phosphatidylserine exposure. Proc. Natl Acad. Sci. USA 113, 9509–9514 (2016).
Suzuki, J., Umeda, M., Sims, P. J. & Nagata, S. Calcium-dependent phospholipid scrambling by TMEM16F. Nature 468, 834–838 (2010). This paper identifies a widely expressed PtdSer scramblase that is activated by Ca 2+ binding.
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). This paper identifies a widely expressed PtdSer scramblase that is activated by caspase cleavage.
Suzuki, J., Imanishi, E. & Nagata, S. Exposure of phosphatidylserine by Xk-related protein family members during apoptosis. J. Biol. Chem. 289, 30257–30267 (2014).
Bevers, E. M. & Williamson, P. L. Getting to the outer leaflet: physiology of phosphatidylserine exposure at the plasma membrane. Physiol. Rev. 96, 605–645 (2016).
Yu, K. et al. Identification of a lipid scrambling domain in ANO6/TMEM16F. eLife 4, e06901 (2015).
Watanabe, R., Sakuragi, T., Noji, H. & Nagata, S. Single-molecule analysis of phospholipid scrambling by TMEM16F. Proc. Natl Acad. Sci. USA 115, 3066–3071 (2018).
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).
Freeman, G. J., Casasnovas, J. M., Umetsu, D. T. & DeKruyff, R. H. TIM genes: a family of cell surface phosphatidylserine receptors that regulate innate and adaptive immunity. Immunol. Rev. 235, 172–189 (2010).
Lemke, G. Biology of the TAM receptors. Cold Spring Harb. Perspect. Biol. 5, a009076 (2013).
Miyanishi, M. et al. Identification of Tim4 as a phosphatidylserine receptor. Nature 450, 435–439 (2007). This paper describes TIM4 as a direct PtdSer binder.
Yanagihashi, Y., Segawa, K., Maeda, R., Nabeshima, Y. I. & Nagata, S. Mouse macrophages show different requirements for phosphatidylserine receptor Tim4 in efferocytosis. Proc. Natl Acad. Sci. USA 114, 8800–8805 (2017).
Flannagan, R. S., Canton, J., Furuya, W., Glogauer, M. & Grinstein, S. The phosphatidylserine receptor TIM4 utilizes integrins as coreceptors to effect phagocytosis. Mol. Biol. Cell 25, 1511–1522 (2014).
Wong, K. et al. Phosphatidylserine receptor Tim-4 is essential for the maintenance of the homeostatic state of resident peritoneal macrophages. Proc. Natl Acad. Sci. USA 107, 8712–8717 (2010).
Rodriguez-Manzanet, R. et al. T and B cell hyperactivity and autoimmunity associated with niche-specific defects in apoptotic body clearance in TIM-4-deficient mice. Proc. Natl Acad. Sci. USA 107, 8706–8711 (2010).
Santiago, C. et al. Structures of T cell immunoglobulin mucin protein 4 show a metal-Ion-dependent ligand binding site where phosphatidylserine binds. Immunity 27, 941–951 (2007).
DeKruyff, R. H. et al. T cell/transmembrane, Ig, and mucin-3 allelic variants differentially recognize phosphatidylserine and mediate phagocytosis of apoptotic cells. J. Immunol. 184, 1918–1930 (2010).
Tietjen, G. T. et al. Molecular mechanism for differential recognition of membrane phosphatidylserine by the immune regulatory receptor Tim4. Proc. Natl Acad. Sci. USA 111, E1463–E1472 (2014).
Lemke, G. & Rothlin, C. V. Immunobiology of the TAM receptors. Nat. Rev. Immunol. 8, 327–336 (2008).
Lew, E. D. et al. Differential TAM receptor-ligand-phospholipid interactions delimit differential TAM bioactivities. eLife 3, e03385 (2014). This paper establishes the rules of engagement for TAM receptors and their ligands.
Stitt, T. N. et al. The anticoagulation factor protein S and its relative, Gas6, are ligands for the Tyro 3/Axl family of receptor tyrosine kinases. Cell 80, 661–670 (1995).
Dransfield, I., Zagorska, A., Lew, E. D., Michail, K. & Lemke, G. Mer receptor tyrosine kinase mediates both tethering and phagocytosis of apoptotic cells. Cell Death Dis. 6, e1646 (2015).
Zagórska, A., Través, P. G., Lew, E. D., Dransfield, I. & Lemke, G. Diversification of TAM receptor tyrosine kinase function. Nat. Immunol. 15, 920–928 (2014). This paper identifies MER and AXL as mediators of efferocytosis under homeostatic and inflammatory conditions, respectively.
Lemke, G. Phosphatidylserine is the signal for TAM receptors and their ligands. Trends Biochem. Sci. 42, 738–748 (2017).
Rothlin, C. V., Carrera-Silva, E. A., Bosurgi, L. & Ghosh, S. TAM receptor signaling in immune homeostasis. Annu. Rev. Immunol. 33, 355–391 (2015).
Fujimori, T. et al. The Axl receptor tyrosine kinase is a discriminator of macrophage function in the inflamed lung. Mucosal Immunol. 8, 1021–1030 (2015).
Tsou, W. I. et al. Receptor tyrosine kinases, TYRO3, AXL and MER, demonstrate distinct patterns and complex regulation of ligand-induced activation. J. Biol. Chem. 289, 25750–25763 (2014).
Scott, R. S. et al. Phagocytosis and clearance of apoptotic cells is mediated by MER. Nature 411, 207–211 (2001). This paper provides the first evidence for MER as a mediator of efferocytosis.
Grabiec, A. M., Goenka, A., Fife, M. E., Fujimori, T. & Hussell, T. Axl and MerTK receptor tyrosine kinases maintain human macrophage efferocytic capacity in the presence of viral triggers. Eur. J. Immunol. 48, 855–860 (2018).
Cohen, P. L. et al. Delayed apoptotic cell clearance and lupus-like autoimmunity in mice lacking the c-mer membrane tyrosine kinase. J. Exp. Med. 196, 135–140 (2002).
Thorp, E., Cui, D., Schrijvers, D. M., Kuriakose, G. & Tabas, I. Mertk receptor mutation reduces efferocytosis efficiency and promotes apoptotic cell accumulation and plaque necrosis in atherosclerotic lesions of apoe−/− mice. Arterioscler. Thromb. Vasc. Biol. 28, 1421–1428 (2008).
A-Gonzalez, N. et al. Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR. Immunity 31, 245–258 (2009).
Toda, S., Segawa, K. & Nagata, S. MerTK-mediated engulfment of pyrenocytes by central macrophages in erythroblastic islands. Blood 123, 3963–3971 (2014).
Ancot, F., Foveau, B., Lefebvre, J., Leroy, C. & Tulasne, D. Proteolytic cleavages give receptor tyrosine kinases the gift of ubiquity. Oncogene 28, 2185–2195 (2009).
Orme, J. J. et al. Heightened cleavage of Axl receptor tyrosine kinase by ADAM metalloproteases may contribute to disease pathogenesis in SLE. Clin. Immunol. 169, 58–68 (2016).
Dengler, M. et al. Accurate determination of soluble Axl by enzyme-linked immunosorbent assay. Assay Drug Dev. Technol. 14, 543–550 (2016).
Rothlin, C. V., Ghosh, S., Zuniga, E. I., Oldstone, M. B. & Lemke, G. TAM receptors are pleiotropic inhibitors of the innate immune response. Cell 131, 1124–1136 (2007).This paper delineates a mechanism whereby AXL functions as an intrinsic negative feedback inhibitor of the innate immune response in DCs.
Chan, P. Y. et al. The TAM family receptor tyrosine kinase TYRO3 is a negative regulator of type 2 immunity. Science 352, 99–103 (2016).
Lu, Q. et al. Tyro-3 family receptors are essential regulators of mammalian spermatogenesis. Nature 398, 723–728 (1999).
Lu, Q. & Lemke, G. Homeostatic regulation of the immune system by receptor tyrosine kinases of the Tyro 3 family. Science 293, 306–311 (2001).This paper describes TAM receptor expression in macrophages and the autoimmune phenotypes that appear in mice with mutations in TAM receptor genes.
Khan, T. N., Wong, E. B., Soni, C. & Rahman, Z. S. Prolonged apoptotic cell accumulation in germinal centers of Mer-deficient mice causes elevated B cell and CD4+ Th cell responses leading to autoantibody production. J. Immunol. 190, 1433–1446 (2013).
Lemke, G. & Lu, Q. Macrophage regulation by Tyro 3 family receptors. Curr. Opin. Immunol. 15, 31–36 (2003).
Schell, S. L. et al. Mer receptor tyrosine kinase signaling prevents self-ligand sensing and aberrant selection in germinal centers. J. Immunol. 199, 4001–4015 (2017).
Wallet, M. A. et al. MerTK is required for apoptotic cell-induced T cell tolerance. J. Exp. Med. 205, 219–232 (2008).
Kaminska, A., Enguita, F. J. & Stepien, E. L. Lactadherin: an unappreciated haemostasis regulator and potential therapeutic agent. Vascul. Pharmacol. 101, 21–28 (2018).
Hanayama, R. et al. Identification of a factor that links apoptotic cells to phagocytes. Nature 417, 182–187 (2002). This paper identifies MFGE8 as a soluble bridging protein that binds to PtdSer.
Hanayama, R. et al. Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice. Science 304, 1147–1150 (2004).
Akakura, S. et al. The opsonin MFG-E8 is a ligand for the alphavbeta5 integrin and triggers DOCK180-dependent Rac1 activation for the phagocytosis of apoptotic cells. Exp. Cell Res. 292, 403–416 (2004).
Raymond, A., Ensslin, M. A. & Shur, B. D. SED1/MFG-E8: a bi-motif protein that orchestrates diverse cellular interactions. J. Cell. Biochem. 106, 957–966 (2009).
Peng, Y. & Elkon, K. B. Autoimmunity in MFG-E8-deficient mice is associated with altered trafficking and enhanced cross-presentation of apoptotic cell antigens. J. Clin. Invest. 121, 2221–2241 (2011).
Lauber, K. et al. Milk fat globule-EGF factor 8 mediates the enhancement of apoptotic cell clearance by glucocorticoids. Cell Death Differ. 20, 1230–1240 (2013).
Murakami, Y. et al. CD300b regulates the phagocytosis of apoptotic cells via phosphatidylserine recognition. Cell Death Differ. 21, 1746–1757 (2014).
Borrego, F. The CD300 molecules: an emerging family of regulators of the immune system. Blood 121, 1951–1960 (2013).
Park, D. et al. BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module. Nature 450, 430–434 (2007).
Das, S. et al. Brain angiogenesis inhibitor 1 (BAI1) is a pattern recognition receptor that mediates macrophage binding and engulfment of Gram-negative bacteria. Proc. Natl Acad. Sci. USA 108, 2136–2141 (2011).
Zhu, D. et al. BAI1 regulates spatial learning and synaptic plasticity in the hippocampus. J. Clin. Invest. 125, 1497–1508 (2015).
Lee, C. S. et al. Boosting apoptotic cell clearance by colonic epithelial cells attenuates inflammation in vivo. Immunity 44, 807–820 (2016).
Park, S. Y. et al. Rapid cell corpse clearance by stabilin-2, a membrane phosphatidylserine receptor. Cell Death Differ. 15, 192–201 (2008).
Kim, S. et al. Cross talk between engulfment receptors stabilin-2 and integrin alphavbeta5 orchestrates engulfment of phosphatidylserine-exposed erythrocytes. Mol. Cell. Biol. 32, 2698–2708 (2012).
Taylor, P. R. et al. A hierarchical role for classical pathway complement proteins in the clearance of apoptotic cells in vivo. J. Exp. Med. 192, 359–366 (2000).
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).
Galvan, M. D., Greenlee-Wacker, M. C. & Bohlson, S. S. C1q and phagocytosis: the perfect complement to a good meal. J. Leukoc. Biol. 92, 489–497 (2012).
Martin, M. & Blom, A. M. Complement in removal of the dead — balancing inflammation. Immunol. Rev. 274, 218–232 (2016).
Paidassi, H. et al. C1q binds phosphatidylserine and likely acts as a multiligand-bridging molecule in apoptotic cell recognition. J. Immunol. 180, 2329–2338 (2008).
Stegert, M., Bock, M. & Trendelenburg, M. Clinical presentation of human C1q deficiency: how much of a lupus? Mol. Immunol. 67, 3–11 (2015).
Clarke, E. V., Weist, B. M., Walsh, C. M. & Tenner, A. J. Complement protein C1q bound to apoptotic cells suppresses human macrophage and dendritic cell-mediated Th17 and Th1 T cell subset proliferation. J. Leukoc. Biol. 97, 147–160 (2015).
Kenyon, K. D. et al. IgG autoantibodies against deposited C3 inhibit macrophage-mediated apoptotic cell engulfment in systemic autoimmunity. J. Immunol. 187, 2101–2111 (2011).
Mevorach, D., Mascarenhas, J. O., Gershov, D. & Elkon, K. B. Complement-dependent clearance of apoptotic cells by human macrophages. J. Exp. Med. 188, 2313–2320 (1998).
Suh, C. H., Hilliard, B., Li, S., Merrill, J. T. & Cohen, P. L. TAM receptor ligands in lupus: protein S but not Gas6 levels reflect disease activity in systemic lupus erythematosus. Arthritis Res. Ther. 12, R146 (2010).
Gao, A. G. et al. Integrin-associated protein is a receptor for the C-terminal domain of thrombospondin. J. Biol. Chem. 271, 21–24 (1996).
Brown, E. J. & Frazier, W. A. Integrin-associated protein (CD47) and its ligands. Trends Cell Biol. 11, 130–135 (2001).
Oldenborg, P. A. et al. Role of CD47 as a marker of self on red blood cells. Science 288, 2051–2054 (2000).
Barclay, A. N. & Van den Berg, T. K. The interaction between signal regulatory protein alpha (SIRPalpha) and CD47: structure, function, and therapeutic target. Annu. Rev. Immunol. 32, 25–50 (2014).
Bian, Z. et al. Cd47-Sirpalpha interaction and IL-10 constrain inflammation-induced macrophage phagocytosis of healthy self-cells. Proc. Natl Acad. Sci. USA 113, E5434–E5443 (2016).
Jaiswal, S. et al. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell 138, 271–285 (2009).
Chao, M. P. et al. Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell 142, 699–713 (2010).
Horrigan, S. K. & Reproducibility Project: Cancer Biology. Replication study: the CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. eLife 6, e18173 (2017).
Russ, A. et al. Blocking “don’t eat me” signal of CD47-SIRPalpha in hematological malignancies, an in-depth review. Blood Rev. 32, 480–489 (2018).
Lehrman, E. K. et al. CD47 protects synapses from excess microglia-mediated pruning during development. Neuron 100, 120–134 (2018).
Gumienny, T. L. et al. CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway, is required for phagocytosis and cell migration. Cell 107, 27–41 (2001).
Tosello-Trampont, A. C., Brugnera, E. & Ravichandran, K. S. Evidence for a conserved role for CRKII and Rac in engulfment of apoptotic cells. J. Biol. Chem. 276, 13797–13802 (2001).
Leverrier, Y. & Ridley, A. J. Requirement for Rho GTPases and PI 3-kinases during apoptotic cell phagocytosis by macrophages. Curr. Biol. 11, 195–199 (2001).
Kitano, M., Nakaya, M., Nakamura, T., Nagata, S. & Matsuda, M. Imaging of Rab5 activity identifies essential regulators for phagosome maturation. Nature 453, 241–245 (2008).
Fond, A. M. & Ravichandran, K. S. Clearance of dying cells by phagocytes: mechanisms and implications for disease pathogenesis. Adv. Exp. Med. Biol 930, 25–49 (2016).
Park, S. Y. & Kim, I. S. Engulfment signals and the phagocytic machinery for apoptotic cell clearance. Exp. Mol. Med. 49, e331 (2017).
Hochreiter-Hufford, A. & Ravichandran, K. S. Clearing the dead: apoptotic cell sensing, recognition, engulfment, and digestion. Cold Spring Harb. Perspect. Biol. 5, a008748 (2013).
Hoeppner, D. J., Hengartner, M. O. & Schnabel, R. Engulfment genes cooperate with ced-3 to promote cell death in Caenorhabditis elegans. Nature 412, 202–206 (2001).
Reddien, P. W., Cameron, S. & Horvitz, H. R. Phagocytosis promotes programmed cell death in C. elegans. Nature 412, 198–202 (2001).
Tufail, Y. et al. Phosphatidylserine exposure controls viral innate immune responses by microglia. Neuron 93, 574–586 (2017).
Neher, J. J. et al. Phagocytosis executes delayed neuronal death after focal brain ischemia. Proc. Natl Acad. Sci. USA 110, E4098–E4107 (2013). This paper provides in vivo evidence that live neurons may be phagocytosed by microglia in a MER-dependent process.
Brelstaff, J., Tolkovsky, A. M., Ghetti, B., Goedert, M. & Spillantini, M. G. Living neurons with Tau filaments aberrantly expose phosphatidylserine and are phagocytosed by microglia. Cell Rep. 24, 1939–1948 (2018).
Fricker, M. et al. MFG-E8 mediates primary phagocytosis of viable neurons during neuroinflammation. J. Neurosci. 32, 2657–2666 (2012).
Chua, B. A. et al. Protein S and Gas6 induce efferocytosis of HIV-1-infected cells. Virology 515, 176–190 (2018).
Brown, G. C. & Neher, J. J. Microglial phagocytosis of live neurons. Nat. Rev. Neurosci. 15, 209–216 (2014).
Fricker, M., Tolkovsky, A. M., Borutaite, V., Coleman, M. & Brown, G. C. Neuronal cell death. Physiol. Rev. 98, 813–880 (2018).
Strauss, O. The retinal pigment epithelium in visual function. Physiol. Rev. 85, 845–881 (2005).
Sparrow, J. R., Hicks, D. & Hamel, C. P. The retinal pigment epithelium in health and disease. Curr. Mol. Med. 10, 802–823 (2010).
D’Cruz, P. M. et al. Mutation of the receptor tyrosine kinase gene Mertk in the retinal dystrophic RCS rat. Hum. Mol. Genet. 9, 645–651 (2000).
Duncan, J. L. et al. An RCS-like retinal dystrophy phenotype in mer knockout mice. Invest. Ophthalmol. Vis. Sci. 44, 826–838 (2003).
Gal, A. et al. Mutations in MERTK, the human orthologue of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa. Nat. Genet. 26, 270–271 (2000). This paper describes the first of a series of human MERTK mutations that result in retinal dystrophies.
Audo, I. et al. MERTK mutation update in inherited retinal diseases. Hum. Mutat. 39, 887–913 (2018).
Ghazi, N. G. et al. Treatment of retinitis pigmentosa due to MERTK mutations by ocular subretinal injection of adeno-associated virus gene vector: results of a phase I trial. Hum. Genet. 135, 327–343 (2016).
Burstyn-Cohen, T. et al. Genetic dissection of TAM receptor-ligand interaction in retinal pigment epithelial cell phagocytosis. Neuron 76, 1123–1132 (2012).
Nandrot, E. F. & Finnemann, S. C. Lack of alphavbeta5 integrin receptor or its ligand MFG-E8: distinct effects on retinal function. Ophthalm. Res. 40, 120–123 (2008).
Ruggiero, L., Connor, M. P., Chen, J., Langen, R. & Finnemann, S. C. Diurnal, localized exposure of phosphatidylserine by rod outer segment tips in wild-type but not Itgb5−/− or Mfge8−/− mouse retina. Proc. Natl Acad. Sci. USA 109, 8145–8148 (2012). This paper presents evidence that localized PtdSer externalization specifies the localized phagocytic excision of photoreceptor outer segments.
Hong, S., Dissing-Olesen, L. & Stevens, B. New insights on the role of microglia in synaptic pruning in health and disease. Curr. Opin. Neurobiol. 36, 128–134 (2016).
Thion, M. S. & Garel, S. Microglia under the spotlight: activity and complement-dependent engulfment of synapses. Trends Neurosci. 41, 332–334 (2018).
Schafer, D. P. et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74, 691–705 (2012). This paper describes a role for complement decoration of presynaptic neuronal elements that are phagocytosed by microglia.
Presumey, J., Bialas, A. R. & Carroll, M. C. Complement system in neural synapse elimination in development and disease. Adv. Immunol. 135, 53–79 (2017).
Sekar, A. et al. Schizophrenia risk from complex variation of complement component 4. Nature 530, 177–183 (2016).
Gyorffy, B. A. et al. Local apoptotic-like mechanisms underlie complement-mediated synaptic pruning. Proc. Natl Acad. Sci. USA 115, 6303–6308 (2018).
Bhattacharyya, S. et al. Enveloped viruses disable innate immune responses in dendritic cells by direct activation of TAM receptors. Cell Host Microbe 14, 136–147 (2013).
Moller-Tank, S. & Maury, W. Phosphatidylserine receptors: enhancers of enveloped virus entry and infection. Virology 468–470, 565–580 (2014).
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).
Yurdagul, A. et al. Mechanisms and consequences of defective efferocytosis in atherosclerosis. Front. Cardiovasc. Med. 4, 86 (2017).
Grabiec, A. M. & Hussell, T. The role of airway macrophages in apoptotic cell clearance following acute and chronic lung inflammation. Semin. Immunopathol. 38, 409–423 (2016).
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).
Schoumacher, M. & Burbridge, M. Key roles of AXL and MER receptor tyrosine kinases in resistance to multiple anticancer therapies. Curr. Oncol. Rep. 19, 19 (2017).
The author thanks the members of his laboratory for comments and discussions. This work is supported by grants from the US National Institutes of Health (NIH) (AI101400, NS085296 and AG060748), the Cure Alzheimer’s Fund and the Leona M. and Harry B. Helmsley Charitable Trust.
Nature Reviews Immunology thanks S. Grinstein and the other anonymous reviewer(s) for their contribution to the peer review of this work.
The author declares no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- NIH3T3 cells
A cell line derived from mouse embryonic fibroblasts.
- AD293 cells
A cell line derived from the HEK293 human embryonic kidney cell line.
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