Human bodies collectively turn over about 200 billion to 300 billion cells every day. Such turnover is an integral part of embryonic and postnatal development, as well as routine tissue homeostasis. This process involves the induction of programmed cell death in specific cells within the tissues and the specific recognition and removal of dying cells by a clearance 'crew' composed of professional, non-professional and specialized phagocytes. In the past few years, considerable progress has been made in identifying many features of apoptotic cell clearance. Some of these new observations challenge the way dying cells themselves are viewed, as well as how healthy cells interact with and respond to dying cells. Here we focus on the homeostatic removal of apoptotic cells in tissues.
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Nagata, S., Hanayama, R. & Kawane, K. Autoimmunity and the clearance of dead cells. Cell 140, 619–630 (2010).
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).
Monks, J. et al. Epithelial cells as phagocytes: apoptotic epithelial cells are engulfed by mammary alveolar epithelial cells and repress inflammatory mediator release. Cell Death Differ. 12, 107–114 (2005).
Nagata, S. Autoimmune diseases caused by defects in clearing dead cells and nuclei expelled from erythroid precursors. Immunol. Rev. 220, 237–250 (2007).
Metchnikoff, E. in Lectures on the Comparative Pathology of Inflammation (Dover, New York, 1968).
van Furth, R. et al. The mononuclear phagocyte system: a new classification of macrophages, monocytes, and their precursor cells. Bull. World Health Organ. 46, 845–852 (1972).
Lavin, Y. & Merad, M. Macrophages: gatekeepers of tissue integrity. Cancer Immunol. Res. 1, 201–209 (2013).
Epelman, S., Lavine, K.J. & Randolph, G.J. Origin and functions of tissue macrophages. Immunity 41, 21–35 (2014).
Gomez Perdiguero, E. et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518, 547–551 (2015).
Hoeffel, G. et al. C-myb+ erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages. Immunity 42, 665–678 (2015).
Dini, L., Pagliara, P. & Carla, E.C. Phagocytosis of apoptotic cells by liver: a morphological study. Microsc. Res. Tech. 57, 530–540 (2002).
Bilimoria, P.M. & Stevens, B. Microglia function during brain development: New insights from animal models. Brain Res. 1617, 7–17 (2015).
Uderhardt, S. et al. 12/15-lipoxygenase orchestrates the clearance of apoptotic cells and maintains immunologic tolerance. Immunity 36, 834–846 (2012).
Wood, W. et al. Mesenchymal cells engulf and clear apoptotic footplate cells in macrophageless PU.1 null mouse embryos. Development 127, 5245–5252 (2000).
Juncadella, I.J. et al. Apoptotic cell clearance by bronchial epithelial cells critically influences airway inflammation. Nature 493, 547–551 (2013).
Elliott, M.R. et al. Unexpected requirement for ELMO1 in clearance of apoptotic germ cells in vivo. Nature 467, 333–337 (2010).
Lysiak, J.J., Turner, S.D. & Turner, T.T. Molecular pathway of germ cell apoptosis following ischemia/reperfusion of the rat testis. Biol. Reprod. 63, 1465–1472 (2000).
Burstyn-Cohen, T. et al. Genetic dissection of TAM receptor-ligand interaction in retinal pigment epithelial cell phagocytosis. Neuron 76, 1123–1132 (2012).
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).
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).
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., Wesselborg, S., Herrmann, M. & Lauber, K. Dangerous attraction: phagocyte recruitment and danger signals of apoptotic and necrotic cells. Apoptosis 15, 1007–1028 (2010).
Truman, L.A. et al. CX3CL1/fractalkine is released from apoptotic lymphocytes to stimulate macrophage chemotaxis. Blood 112, 5026–5036 (2008).
Miksa, M., Amin, D., Wu, R., Ravikumar, T.S. & Wang, P. Fractalkine-induced MFG-E8 leads to enhanced apoptotic cell clearance by macrophages. Mol. Med. 13, 553–560 (2007).
Darland-Ransom, M. et al. Role of C. elegans TAT-1 protein in maintaining plasma membrane phosphatidylserine asymmetry. Science 320, 528–531 (2008).
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).
Balasubramanian, K. & Schroit, A.J. Aminophospholipid asymmetry: A matter of life and death. Annu. Rev. Physiol. 65, 701–734 (2003).
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).
Segawa, K. et al. Caspase-mediated cleavage of phospholipid flippase for apoptotic phosphatidylserine exposure. Science 344, 1164–1168 (2014).
Suzuki, J., Umeda, M., Sims, P.J. & Nagata, S. Calcium-dependent phospholipid scrambling by TMEM16F. Nature 468, 834–838 (2010).
Lauber, K., Blumenthal, S.G., Waibel, M. & Wesselborg, S. Clearance of apoptotic cells: getting rid of the corpses. Mol. Cell 14, 277–287 (2004).
Brown, S. et al. Apoptosis disables CD31-mediated cell detachment from phagocytes promoting binding and engulfment. Nature 418, 200–203 (2002).
Simhadri, V.R. et al. Human CD300a binds to phosphatidylethanolamine and phosphatidylserine, and modulates the phagocytosis of dead cells. Blood 119, 2799–2809 (2012).
Barclay, A.N. & Van den Berg, T.K. The interaction between signal regulatory protein α (SIRP α) and CD47: structure, function, and therapeutic target. Annu. Rev. Immunol. 32, 25–50 (2014).
Hamann, J. et al. International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors. Pharmacol. Rev. 67, 338–367 (2015).
Duman, J.G. et al. The adhesion-GPCR BAI1 regulates synaptogenesis by controlling the recruitment of the Par3/Tiam1 polarity complex to synaptic sites. J Neurosci. 33, 6964–6978 (2013).
Hochreiter-Hufford, A.E. et al. Phosphatidylserine receptor BAI1 and apoptotic cells as new promoters of myoblast fusion. Nature 497, 263–267 (2013).
Kaur, B., Brat, D.J., Devi, N.S. & Van Meir, E.G. Vasculostatin, a proteolytic fragment of brain angiogenesis inhibitor 1, is an antiangiogenic and antitumorigenic factor. Oncogene 24, 3632–3642 (2005).
Park, D. et al. BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module. Nature 450, 430–434 (2007).
Zhu, D. et al. BAI1 regulates spatial learning and synaptic plasticity in the hippocampus. J. Clin. Invest. 125, 1497–1508 (2015).
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).
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).
Miyanishi, M. et al. Identification of Tim4 as a phosphatidylserine receptor. Nature 450, 435–439 (2007).
Kobayashi, N. et al. TIM-1 and TIM-4 glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells. Immunity 27, 927–940 (2007).
Park, D., Hochreiter-Hufford, A. & Ravichandran, K.S. The phosphatidylserine receptor TIM-4 does not mediate direct signaling. Curr. Biol. 19, 346–351 (2009).
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).
Mazaheri, F. et al. Distinct roles for BAI1 and TIM-4 in the engulfment of dying neurons by microglia. Nat. Commun. 5, 4046 (2014).
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).
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).
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).
Albacker, L.A. et al. TIM-4, a receptor for phosphatidylserine, controls adaptive immunity by regulating the removal of antigen-specific T cells. J. Immunol. 185, 6839–6849 (2010).
Lemke, G. Biology of the TAM receptors. Cold Spring Harb. Perspect. Biol. 5, a009076 (2013).
Lew, E.D. et al. Differential TAM receptor-ligand-phospholipid interactions delimit differential TAM bioactivities. eLife 10, 7554 (2014).
Zagórska, A., Traves, P.G., Lew, E.D., Dransfield, I. & Lemke, G. Diversification of TAM receptor tyrosine kinase function. Nat. Immunol. 15, 920–928 (2014).
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).
Lu, Q. et al. Tyro-3 family receptors are essential regulators of mammalian spermatogenesis. Nature 398, 723–728 (1999).
Duncan, J.L. et al. An RCS-like retinal dystrophy phenotype in mer knockout mice. Invest. Ophthalmol. Vis. Sci. 44, 826–838 (2003).
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).
Mukundan, L. et al. PPAR-δ senses and orchestrates clearance of apoptotic cells to promote tolerance. Nat. Med. 15, 1266–1272 (2009).
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).
Roszer, T. et al. Autoimmune kidney disease and impaired engulfment of apoptotic cells in mice with macrophage peroxisome proliferator-activated receptor gamma or retinoid X receptor α deficiency. J. Immunol. 186, 621–631 (2011).
Park, D. et al. Continued clearance of apoptotic cells critically depends on the phagocyte Ucp2 protein. Nature 477, 220–224 (2011).
Yoshida, H. et al. Phosphatidylserine-dependent engulfment by macrophages of nuclei from erythroid precursor cells. Nature 437, 754–758 (2005).
Toda, S., Segawa, K. & Nagata, S. MerTK-mediated engulfment of pyrenocytes by central macrophages in erythroblastic islands. Blood 123, 3963–3971 (2014).
Kawane, K. et al. Requirement of DNase II for definitive erythropoiesis in the mouse fetal liver. Science 292, 1546–1549 (2001).
Yoshida, H., Okabe, Y., Kawane, K., Fukuyama, H. & Nagata, S. Lethal anemia caused by interferon-β produced in mouse embryos carrying undigested DNA. Nat. Immunol. 6, 49–56 (2005).
Kawane, K. et al. Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages. Nature 443, 998–1002 (2006).
Marcel, Y.L., Ouimet, M. & Wang, M.D. Regulation of cholesterol efflux from macrophages. Curr. Opin. Lipidol. 19, 455–461 (2008).
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).
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).
Janko, C. et al. CRP/anti-CRP antibodies assembly on the surfaces of cell remnants switches their phagocytic clearance toward inflammation. Frontiers in immunology 2, 70 (2011).
Poon, I.K., Hulett, M.D. & Parish, C.R. Molecular mechanisms of late apoptotic/necrotic cell clearance. Cell Death Differ. 17, 381–397 (2010).
Zhang, Y., Brenner, M., Yang, W.L. & Wang, P. Recombinant human MFG-E8 ameliorates colon damage in DSS- and TNBS-induced colitis in mice. Lab. Invest. 95, 480–490 (2015).
Gatza, E. et al. Extracorporeal photopheresis reverses experimental graft-versus-host disease through regulatory T cells. Blood 112, 1515–1521 (2008).
Pasparakis, M. & Vandenabeele, P. Necroptosis and its role in inflammation. Nature 517, 311–320 (2015).
Remijsen, Q. et al. Dying for a cause: NETosis, mechanisms behind an antimicrobial cell death modality. Cell Death Differ. 18, 581–588 (2011).
Schauer, C. et al. Aggregated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines. Nat. Med. 20, 511–517 (2014).
Fan, Y. & Bergmann, A. Apoptosis-induced compensatory proliferation. The Cell is dead. Long live the Cell!. Trends Cell Biol. 18, 467–473 (2008).
Chera, S. et al. Apoptotic cells provide an unexpected source of Wnt3 signaling to drive hydra head regeneration. Dev. Cell 17, 279–289 (2009).
Tseng, A.S., Adams, D.S., Qiu, D., Koustubhan, P. & Levin, M. Apoptosis is required during early stages of tail regeneration in Xenopus laevis. Dev. Biol. 301, 62–69 (2007).
Fuchs, Y. & Steller, H. Programmed cell death in animal development and disease. Cell 147, 742–758 (2011).
Vlaskalin, T., Wong, C.J. & Tsilfidis, C. Growth and apoptosis during larval forelimb development and adult forelimb regeneration in the newt (Notophthalmus viridescens). Dev. Genes Evol. 214, 423–431 (2004).
Li, F. et al. Apoptotic cells activate the “phoenix rising” pathway to promote wound healing and tissue regeneration. Sci. Signal. 3, ra13 (2010).
Rongvaux, A. et al. Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA. Cell 159, 1563–1577 (2014).
Ravichandran, K.S. Find-me and eat-me signals in apoptotic cell clearance: progress and conundrums. J. Exp. Med. 207, 1807–1817 (2010).
Elliott, J.I. et al. Membrane phosphatidylserine distribution as a non-apoptotic signalling mechanism in lymphocytes. Nat. Cell Biol. 7, 808–816 (2005).
Carrera Silva, E.A. et al. T cell-derived protein S engages TAM receptor signaling in dendritic cells to control the magnitude of the immune response. Immunity 39, 160–170 (2013).
Martin, S. et al. Immunologic stimulation of mast cells leads to the reversible exposure of phosphatidylserine in the absence of apoptosis. Int. Arch. Allergy Immunol. 123, 249–258 (2000).
Frasch, S.C. et al. Phospholipid flip-flop and phospholipid scramblase 1 (PLSCR1) co-localize to uropod rafts in formylated Met-Leu-Phe-stimulated neutrophils. J. Biol. Chem. 279, 17625–17633 (2004).
van den Eijnde, S.M. et al. Transient expression of phosphatidylserine at cell-cell contact areas is required for myotube formation. J. Cell Sci. 114, 3631–3642 (2001).
Hamoud, N., Tran, V., Croteau, L.P., Kania, A. & Cote, J.F. G-protein coupled receptor BAI3 promotes myoblast fusion in vertebrates. Proc. Natl. Acad. Sci. USA 111, 3745–3750 (2014).
Wanderley, J.L., Moreira, M.E., Benjamin, A., Bonomo, A.C. & Barcinski, M.A. Mimicry of apoptotic cells by exposing phosphatidylserine participates in the establishment of amastigotes of Leishmania (L) amazonensis in mammalian hosts. J. Immunol. 176, 1834–1839 (2006).
Seabra, S.H., de Souza, W. & Damatta, R.A. Toxoplasma gondii exposes phosphatidylserine inducing a TGF-β1 autocrine effect orchestrating macrophage evasion. Biochem. Biophys. Res. Commun. 324, 744–752 (2004).
Damatta, R.A. et al. Trypanosoma cruzi exposes phosphatidylserine as an evasion mechanism. FEMS Microbiol. Lett. 266, 29–33 (2007).
Mercer, J. & Helenius, A. Vaccinia virus uses macropinocytosis and apoptotic mimicry to enter host cells. Science 320, 531–535 (2008).
Callahan, M.K. et al. Phosphatidylserine on HIV envelope is a cofactor for infection of monocytic cells. J. Immunol. 170, 4840–4845 (2003).
Brindley, M.A. et al. Tyrosine kinase receptor Axl enhances entry of Zaire ebolavirus without direct interactions with the viral glycoprotein. Virology 415, 83–94 (2011).
Hunt, C.L., Kolokoltsov, A.A., Davey, R.A. & Maury, W. The Tyro3 receptor kinase Axl enhances macropinocytosis of Zaire ebolavirus. J. Virol. 85, 334–347 (2011).
Meertens, L. et al. The TIM and TAM families of phosphatidylserine receptors mediate dengue virus entry. Cell Host Microbe 12, 544–557 (2012).
Morizono, K. & Chen, I.S. Role of phosphatidylserine receptors in enveloped virus infection. J. Virol. 88, 4275–4290 (2014).
Chen, Y.H. et al. Phosphatidylserine vesicles enable efficient en bloc transmission of enteroviruses. Cell 160, 619–630 (2015).
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).
N'Diaye, E.N. et al. TREM-2 (triggering receptor expressed on myeloid cells 2) is a phagocytic receptor for bacteria. J. Cell Biol. 184, 215–223 (2009).
Adachi, H. & Tsujimoto, M. FEEL-1, a novel scavenger receptor with in vitro bacteria-binding and angiogenesis-modulating activities. J. Biol. Chem. 277, 34264–34270 (2002).
Means, T.K. et al. Evolutionarily conserved recognition and innate immunity to fungal pathogens by the scavenger receptors SCARF1 and CD36. J. Exp. Med. 206, 637–653 (2009).
Henson, P.M. Dampening inflammation. Nat. Immunol. 6, 1179–1181 (2005).
Colegio, O.R. et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513, 559–563 (2014).
Chung, W.S. et al. Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways. Nature 504, 394–400 (2013).
Gaultier, A. et al. Low-density lipoprotein receptor-related protein 1 is an essential receptor for myelin phagocytosis. J. Cell Sci. 122, 1155–1162 (2009).
Tasdemir-Yilmaz, O.E. & Freeman, M.R. Astrocytes engage unique molecular programs to engulf pruned neuronal debris from distinct subsets of neurons. Genes Dev. 28, 20–33 (2014).
Lu, Z. et al. Phagocytic activity of neuronal progenitors regulates adult neurogenesis. Nat. Cell Biol. 13, 1076–1083 (2011).
García, M. & Vecino, E. Role of Muller glia in neuroprotection and regeneration in the retina. Histol. Histopathol. 18, 1205–1218 (2003).
Kevany, B.M. & Palczewski, K. Phagocytosis of retinal rod and cone photoreceptors. Physiology (Bethesda) 25, 8–15 (2010).
Wu, Y., Singh, S., Georgescu, M.M. & Birge, R.B. A role for Mer tyrosine kinase in alphavbeta5 integrin-mediated phagocytosis of apoptotic cells. J. Cell Sci. 118, 539–553 (2005).
Todt, J.C., Hu, B. & Curtis, J.L. The receptor tyrosine kinase MerTK activates phospholipase C gamma2 during recognition of apoptotic thymocytes by murine macrophages. J. Leukoc. Biol. 75, 705–713 (2004).
Ji, H. et al. T-cell immunoglobulin and mucin domain 4 (TIM-4) signaling in innate immune-mediated liver ischemia-reperfusion injury. Hepatology 60, 2052–2064 (2014).
Karikoski, M. et al. Clever-1/stabilin-1 controls cancer growth and metastasis. Clin. Cancer Res. 20, 6452–6464 (2014).
Hirose, Y. et al. Inhibition of Stabilin-2 elevates circulating hyaluronic acid levels and prevents tumor metastasis. Proc. Natl. Acad. Sci. USA 109, 4263–4268 (2012).
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).
Englert, J.M. et al. A role for the receptor for advanced glycation end products in idiopathic pulmonary fibrosis. Am. J. Pathol. 172, 583–591 (2008).
Englert, J.M. et al. Paradoxical function for the receptor for advanced glycation end products in mouse models of pulmonary fibrosis. Int. J. Clin. Exp. Pathol. 4, 241–254 (2011).
He, M. et al. The role of the receptor for advanced glycation end-products in lung fibrosis. Am. J. Physiol. Lung Cell. Mol. Physiol. 293, L1427–L1436 (2007).
He, M. et al. Receptor for advanced glycation end products binds to phosphatidylserine and assists in the clearance of apoptotic cells. EMBO Rep. 12, 358–364 (2011).
Liliensiek, B. et al. Receptor for advanced glycation end products (RAGE) regulates sepsis but not the adaptive immune response. J. Clin. Invest. 113, 1641–1650 (2004).
Tian, L. et al. p85α recruitment by the CD300f phosphatidylserine receptor mediates apoptotic cell clearance required for autoimmunity suppression. Nat. Commun. 5, 3146 (2014).
Cantoni, C. et al. TREM2 regulates microglial cell activation in response to demyelination in vivo. Acta Neuropathol. 129, 429–447 (2015).
Jay, T.R. et al. TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer's disease mouse models. J. Exp. Med. 212, 287–295 (2015).
Poliani, P.L. et al. TREM2 sustains microglial expansion during aging and response to demyelination. J. Clin. Invest. 125, 2161–2170 (2015).
Wang, Y. et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model. Cell 160, 1061–1071 (2015).
Bosurgi, L. et al. Paradoxical role of the proto-oncogene Axl and Mer receptor tyrosine kinases in colon cancer. Proc. Natl. Acad. Sci. USA 110, 13091–13096 (2013).
Camenisch, T.D., Koller, B.H., Earp, H.S. & Matsushima, G.K. A novel receptor tyrosine kinase, Mer, inhibits TNF-alpha production and lipopolysaccharide-induced endotoxic shock. J. Immunol. 162, 3498–3503 (1999).
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).
Lu, Q. & Lemke, G. Homeostatic regulation of the immune system by receptor tyrosine kinases of the Tyro 3 family. Science 293, 306–311 (2001).
Neher, J.J. et al. Phagocytosis executes delayed neuronal death after focal brain ischemia. Proc. Natl. Acad. Sci. USA 110, E4098–E4107 (2013).
Prasad, D. et al. TAM receptor function in the retinal pigment epithelium. Mol. Cell. Neurosci. 33, 96–108 (2006).
Scott, R.S. et al. Phagocytosis and clearance of apoptotic cells is mediated by MER. Nature 411, 207–211 (2001).
Weinger, J.G. et al. Loss of the receptor tyrosine kinase Axl leads to enhanced inflammation in the CNS and delayed removal of myelin debris during experimental autoimmune encephalomyelitis. J. Neuroinflammation 8, 49 (2011).
Acharya, M. et al. αv Integrin expression by DCs is required for Th17 cell differentiation and development of experimental autoimmune encephalomyelitis in mice. J. Clin. Invest. 120, 4445–4452 (2010).
Lacy-Hulbert, A. et al. Ulcerative colitis and autoimmunity induced by loss of myeloid alphav integrins. Proc. Natl. Acad. Sci. USA 104, 15823–15828 (2007).
McCarty, J.H. et al. Selective ablation of αV integrins in the central nervous system leads to cerebral hemorrhage, seizures, axonal degeneration and premature death. Development 132, 165–176 (2005).
McCarty, J.H. et al. Genetic ablation of αV integrins in epithelial cells of the eyelid skin and conjunctiva leads to squamous cell carcinoma. Am. J. Pathol. 172, 1740–1747 (2008).
Nandrot, E.F. & Finnemann, S.C. Lack of αVβ5 integrin receptor or its ligand MFG-E8: distinct effects on retinal function. Ophthalmic Res. 40, 120–123 (2008).
Aziz, M., Matsuda, A., Yang, W.L., Jacob, A. & Wang, P. Milk fat globule-epidermal growth factor-factor 8 attenuates neutrophil infiltration in acute lung injury via modulation of CXCR2. J. Immunol. 189, 393–402 (2012).
Fricker, M. et al. MFG-E8 mediates primary phagocytosis of viable neurons during neuroinflammation. J. Neurosci. 32, 2657–2666 (2012).
Hanayama, R. et al. Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice. Science 304, 1147–1150 (2004).
Kusunoki, R. et al. Role of milk fat globule-epidermal growth factor 8 in colonic inflammation and carcinogenesis. J. Gastroenterol. http://dx.doi.org/10.1007/s00535-014-1036-x (2015).
Neher, J.J., Neniskyte, U. & Brown, G.C. Primary phagocytosis of neurons by inflamed microglia: potential roles in neurodegeneration. Front. Pharmacol. 3, 27 (2012).
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).
Ait-Oufella, H. et al. Lactadherin deficiency leads to apoptotic cell accumulation and accelerated atherosclerosis in mice. Circulation 115, 2168–2177 (2007).
Akitake-Kawano, R. et al. Inhibitory role of Gas6 in intestinal tumorigenesis. Carcinogenesis 34, 1567–1574 (2013).
Angelillo-Scherrer, A. et al. Deficiency or inhibition of Gas6 causes platelet dysfunction and protects mice against thrombosis. Nat. Med. 7, 215–221 (2001).
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).
Binder, M.D. et al. Gas6 increases myelination by oligodendrocytes and its deficiency delays recovery following cuprizone-induced demyelination. PLoS ONE 6, e17727 (2011).
Burnier, L. et al. Gas6 deficiency in recipient mice of allogeneic transplantation alleviates hepatic graft-versus-host disease. Blood 115, 3390–3397 (2010).
Llacuna, L. et al. Growth arrest-specific protein 6 is hepatoprotective against murine ischemia/reperfusion injury. Hepatology 52, 1371–1379 (2010).
Yanagita, M. et al. Essential role of Gas6 for glomerular injury in nephrotoxic nephritis. J. Clin. Invest. 110, 239–246 (2002).
Cai, L., Wang, Z., Ji, A., Meyer, J.M. & van der Westhuyzen, D.R. Scavenger receptor CD36 expression contributes to adipose tissue inflammation and cell death in diet-induced obesity. PLoS ONE 7, e36785 (2012).
Greenberg, M.E. et al. Oxidized phosphatidylserine-CD36 interactions play an essential role in macrophage-dependent phagocytosis of apoptotic cells. J. Exp. Med. 203, 2613–2625 (2006).
Kennedy, D.J. et al. Dietary cholesterol plays a role in CD36-mediated atherogenesis in LDLR-knockout mice. Arterioscler. Thromb. Vasc. Biol. 29, 1481–1487 (2009).
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).
Overton, C.D., Yancey, P.G., Major, A.S., Linton, M.F. & Fazio, S. Deletion of macrophage LDL receptor-related protein increases atherogenesis in the mouse. Circ. Res. 100, 670–677 (2007).
Yancey, P.G. et al. Macrophage LRP-1 controls plaque cellularity by regulating efferocytosis and Akt activation. Arterioscler. Thromb. Vasc. Biol. 30, 787–795 (2010).
Yancey, P.G. et al. Low-density lipoprotein receptor-related protein 1 prevents early atherosclerosis by limiting lesional apoptosis and inflammatory Ly-6Chigh monocytosis: evidence that the effects are not apolipoprotein E dependent. Circulation 124, 454–464 (2011).
Subramanian, M. et al. An AXL/LRP-1/RANBP9 complex mediates DC efferocytosis and antigen cross-presentation in vivo. J. Clin. Invest. 124, 1296–1308 (2014).
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).
Bhatia, V.K. et al. Complement C1q reduces early atherosclerosis in low-density lipoprotein receptor-deficient mice. Am. J. Pathol. 170, 416–426 (2007).
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).
Botto, M. et al. Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nat. Genet. 19, 56–59 (1998).
Chu, Y. et al. Enhanced synaptic connectivity and epilepsy in C1q knockout mice. Proc. Natl. Acad. Sci. USA 107, 7975–7980 (2010).
Stevens, B. et al. The classical complement cascade mediates CNS synapse elimination. Cell 131, 1164–1178 (2007).
We thank the members of the Ravichandran laboratory, as well as colleagues in the field, for comments and discussions. Supported by the US National Institutes of Health (NIGMS GM064709, HD074981, GM107848, HL120840 and MH096484).
The authors declare no competing financial interests.
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Arandjelovic, S., Ravichandran, K. Phagocytosis of apoptotic cells in homeostasis. Nat Immunol 16, 907–917 (2015). https://doi.org/10.1038/ni.3253
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