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Phagocytosis: Phenotypically Simple Yet a Mechanistically Complex Process

Phagocytosis is a very complex but crucial process playing a pivotal role in embryonic development and host defense to maintain immune homeostasis

Pages 118-150 | Received 29 Nov 2019, Accepted 13 Feb 2020, Published online: 06 Mar 2020

References

  • Kumar V. Innate lymphoid cells: new paradigm in immunology of inflammation. Immunol Lett. 2014;157(1–2):23–37. doi:10.1016/j.imlet.2013.11.003.
  • Kumar V. Innate lymphoid cells: immunoregulatory cells of mucosal inflammation. Eur J Inflamm. 2014;12(1):11–20. doi:10.1177/1721727X1401200102.
  • Kumar V. Dendritic cells in sepsis: potential immunoregulatory cells with therapeutic potential. Mol Immunol. 2018;101:615–626. doi:10.1016/j.molimm.2018.07.007.
  • Kumar V. Natural killer cells in sepsis: underprivileged innate immune cells. Eur J Cell Biol. 2018;98:81–93. doi:10.1016/j.ejcb.2018.12.003.
  • Kumar V, Ahmad A. Role of MAIT cells in the immunopathogenesis of inflammatory diseases: new players in old game. Int Rev Immunol. 2018;37(2):90–110. doi:10.1080/08830185.2017.1380199.
  • Kumar V, Sharma A. Mast cells: emerging sentinel innate immune cells with diverse role in immunity. Mol Immunol. 2010;48(1–3):14–25. doi:10.1016/j.molimm.2010.07.009.
  • Kumar V, Sharma A. Neutrophils: Cinderella of innate immune system. Int Immunopharmacol. 2010;10(11):1325–1334. doi:10.1016/j.intimp.2010.08.012.
  • Kumar V. The complement system, toll-like receptors and inflammasomes in host defense: three musketeers’ one target. Int Rev Immunol. 2019;38(1):1–26. doi:10.1080/08830185.2019.1609962.
  • Chirumbolo S, Bjorklund G, Sboarina A, Vella A. The role of basophils as innate immune regulatory cells in allergy and immunotherapy. Hum Vaccin Immunother. 2018;14(4):815–831. doi:10.1080/21645515.2017.1417711.
  • Kita H. Eosinophils: multifaceted biological properties and roles in health and disease. Immunol Rev. 2011;242(1):161–177. doi:10.1111/j.1600-065X.2011.01026.x.
  • Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature. 2013;496(7446):445–455. doi:10.1038/nature12034.
  • Branzk N, Gronke K, Diefenbach A. Innate lymphoid cells, mediators of tissue homeostasis, adaptation and disease tolerance. Immunol Rev. 2018;286(1):86–101. doi:10.1111/imr.12718.
  • Galloway DA, Phillips AEM, Owen DRJ, Moore CS. Phagocytosis in the brain: homeostasis and disease. Front Immunol. 2019;10:790. doi:10.3389/fimmu.2019.01575.
  • Hirayama D, Iida T, Nakase H. The phagocytic function of macrophage-enforcing innate immunity and tissue homeostasis. Int J Mol Sci. 2017;19(1):92.
  • Hirsch JG. Phagocytosis. Annu Rev Microbiol. 1965;19(1):339–350. doi:10.1146/annurev.mi.19.100165.002011.
  • Gordon S. Elie Metchnikoff: father of natural immunity. Eur J Immunol. 2008;38(12):3257–3264. doi:10.1002/eji.200838855.
  • Kaufmann SH. Immunology’s foundation: the 100-year anniversary of the Nobel Prize to Paul Ehrlich and Elie Metchnikoff. Nat Immunol. 2008;9(7):705–712. doi:10.1038/ni0708-705.
  • Henderson J. The Plato of Praed Street: the life and times of Almroth Wright. J R Soc Med. 2001;94(7):364–365. doi:10.1177/014107680109400718.
  • Gordon S. The macrophage: past, present and future. Eur J Immunol. 2007;37(S1):S9–S17. doi:10.1002/eji.200737638.
  • Lim JJ, Grinstien S, Roth Z. Diversity and versatility of phagocytosis: roles in innate immunity, tissue remodeling, and homeostasis. Front Cell Infect Microbiol. 2017;7:191.
  • Brown GC, Vilalta A, Fricker M. Phagoptosis - cell death by phagocytosis - plays central roles in physiology, host defense and pathology. Curr Mol Med. 2015;15(9):842–851. doi:10.2174/156652401509151105130628.
  • Brown GC, Neher JJ. Eaten alive! Cell death by primary phagocytosis: ‘phagoptosis. Trends Biochem Sci. 2012;37(8):325–332. doi:10.1016/j.tibs.2012.05.002.
  • Flannagan RS, Jaumouille V, Grinstein S. The cell biology of phagocytosis. Annu Rev Pathol Mech Dis. 2012;7(1):61–98. doi:10.1146/annurev-pathol-011811-132445.
  • Gordon S. Phagocytosis: an immunobiologic process. Immunity. 2016;44(3):463–475. doi:10.1016/j.immuni.2016.02.026.
  • Rabinovitch M. Professional and non-professional phagocytes: an introduction. Trends Cell Biol. 1995;5(3):85–87. doi:10.1016/S0962-8924(00)88955-2.
  • Chow A, Brown BD, Merad M. Studying the mononuclear phagocyte system in the molecular age. Nat Rev Immunol. 2011;11(11):788–798. doi:10.1038/nri3087.
  • Hume DA, Irvine KM, Pridans C. The mononuclear phagocyte system: the relationship between monocytes and macrophages. Trends Immunol. 2019;40(2):98–112. doi:10.1016/j.it.2018.11.007.
  • Kumar V. Macrophages: the potent immunoregulatory innate immune cells. IntechOpen. 2019. doi:10.5772/intechopen.88013.
  • Silva MT. When two is better than one: macrophages and neutrophils work in concert in innate immunity as complementary and cooperative partners of a myeloid phagocyte system. J Leukocyte Biol. 2010;87(1):93–106. doi:10.1189/jlb.0809549.
  • Silva M, Correia-Neves M. Neutrophils and macrophages: the main partners of phagocyte cell systems. Front Immun. 2012;3:174. doi:10.3389/fimmu.2012.00174.
  • Taylor PR, Martinez-Pomares L, Stacey M, Lin HH, Brown GD, Gordon S. Macrophage receptors and immune recognition. Annu Rev Immunol. 2005;23(1):901–944. doi:10.1146/annurev.immunol.23.021704.115816.
  • Grabowska J, Lopez-Venegas MA, Affandi AJ, den Haan JMM. CD169+ Macrophages capture and dendritic cells instruct: the interplay of the gatekeeper and the general of the immune system. Front Immunol. 2018;9:2472. doi:10.3389/fimmu.2018.02472.
  • Geijtenbeek TB, Groot PC, Nolte MA, et al. Marginal zone macrophages express a murine homologue of DC-SIGN that captures blood-borne antigens in vivo. Blood. 2002;100(8):2908–2916., doi:10.1182/blood-2002-04-1044.
  • Borges da Silva H, Fonseca R, Pereira RM, Cassado ADA, Álvarez JM, D’Império Lima MR. Splenic macrophage subsets and their function during blood-borne infections. Front Immunol. 2015;6:480–480. doi:10.3389/fimmu.2015.00480.
  • Koppel EA, Wieland CW, van den Berg VC, et al. Specific ICAM-3 grabbing nonintegrin-related 1 (SIGNR1) expressed by marginal zone macrophages is essential for defense against pulmonary Streptococcus pneumoniae infection. Eur J Immunol. 2005;35(10):2962–2969., doi:10.1002/eji.200526216.
  • Delamarre L, Pack M, Chang H, Mellman I, Trombetta ES. Differential lysosomal proteolysis in antigen-presenting cells determines antigen fate. Science (New York, N.Y.). 2005;307(5715):1630–1634. doi:10.1126/science.1108003.
  • Savina A, Amigorena S. Phagocytosis and antigen presentation in dendritic cells. Immunol Rev. 2007;219(1):143–156. doi:10.1111/j.1600-065X.2007.00552.x.
  • Murray PJ, Wynn TA. Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol. 2011;11(11):723–737. doi:10.1038/nri3073.
  • Vashi N, Andrabi SBA, Ghanwat S, Suar M, Kumar D. Ca(2+)-dependent focal exocytosis of golgi-derived vesicles helps phagocytic uptake in macrophages. J Biol Chem. 2017;292(13):5144–5165. doi:10.1074/jbc.M116.743047.
  • Gordon S, Martinez-Pomares L. Physiological roles of macrophages. Pflugers Arch - Eur J Physiol. 2017;469(3–4):365–374. doi:10.1007/s00424-017-1945-7.
  • Lee WL, Harrison RE, Grinstein S. Phagocytosis by neutrophils. Microbes Infect. 2003;5(14):1299–1306. doi:10.1016/j.micinf.2003.09.014.
  • Herant M, Heinrich V, Dembo M. Mechanics of neutrophil phagocytosis: experiments and quantitative models. J Cell Sci. 2006;119(9):1903–1913. doi:10.1242/jcs.02876.
  • Malaviya R, Ross EA, MacGregor JI, et al. Mast cell phagocytosis of FimH-expressing enterobacteria. J Immunol (Baltimore, Md.: 1950). 1994;152(4):1907–1914.,
  • Malaviya R, Twesten NJ, Ross EA, Abraham SN, Pfeifer JD. Mast cells process bacterial Ags through a phagocytic route for class I MHC presentation to T cells. J Immunol (Baltimore, Md.: 1950). 1996;156(4):1490–1496.
  • Urb M, Sheppard DC. The role of mast cells in the defence against pathogens. PLoS Pathog. 2012;8(4):e1002619. doi:10.1371/journal.ppat.1002619.
  • Spicer SS, Simson JA, Farrington JE. Mast cell phagocytosis of red blood cells. Am J Pathol. 1975;80(3):481–498.
  • DELLA Rovere F, Granata A, Monaco M, Basile G. Phagocytosis of cancer cells by mast cells in breast cancer. Anticancer Res. 2009;29(8):3157–3161.
  • Cline MJ, Hanifin J, Lehrer RI. Phagocytosis by human eosinophils. Blood. 1968;32(6):922–934. doi:10.1182/blood.V32.6.922.922.
  • Cohen SG, Sapp TM. Phagocytosis of bacteria by eosinophils in infectious-related asthma. J Allergy. 1969;44(2):113–117. doi:10.1016/0021-8707(69)90007-0.
  • Lichtenstein LM, Marone G, Thomas LL, Malveaux FJ. The role of basophils in inflammatory reactions. J Invest Dermatol. 1978;71(1):65–69. doi:10.1111/1523-1747.ep12544308.
  • Vann JM, Proctor RA. Phagocytosis of bacteria by endothelial cells. In: Wadström T, Eliasson I, Holder I, Ljungh Å, eds. Pathogenesis of Wound and Biomaterial-Associated Infections. London: Springer; 1990:77–85.
  • Xie R, Gao C, Li W, et al. Phagocytosis by macrophages and endothelial cells inhibits procoagulant and fibrinolytic activity of acute promyelocytic leukemia cells. Blood. 2012;119(10):2325–2334. doi:10.1182/blood-2011-06-362186.
  • Altschul R. Endothelium: Its Development, Morphology, Function, and Pathology. New York & London: The Macmillan Co.; 1954.
  • Shimada H, Rajagopalan LE. Rho kinase-2 activation in human endothelial cells drives lysophosphatidic acid-mediated expression of cell adhesion molecules via NF-kappaB p65. J Biol Chem. 2010;285(17):12536–12542. doi:10.1074/jbc.M109.099630.
  • Rengarajan M, Hayer A, Theriot JA. Endothelial cells use a formin-dependent phagocytosis-like process to internalize the bacterium Listeria monocytogenes. PLoS Pathog. 2016;12(5):e1005603. doi:10.1371/journal.ppat.1005603.
  • Breitsprecher D, Goode BL. Formins at a glance. J Cell Sci. 2013;126(1):1–7. doi:10.1242/jcs.107250.
  • Gao C, Xie R, Li W, et al. Endothelial cell phagocytosis of senescent neutrophils decreases procoagulant activity. Thromb Haemost. 2013;109(6):1079–1090., doi:10.1160/TH12-12-0894.
  • Günther J, Seyfert H-M. The first line of defence: insights into mechanisms and relevance of phagocytosis in epithelial cells. Semin Immunopathol. 2018;40(6):555–565. doi:10.1007/s00281-018-0701-1.
  • Monks J, Rosner D, Geske FJ, et al. Epithelial cells as phagocytes: apoptotic epithelial cells are engulfed by mammary alveolar epithelial cells and repress inflammatory mediator release. Cell Death Differ. 2005;12(2):107–114. doi:10.1038/sj.cdd.4401517.
  • Penberthy KK, Juncadella IJ, Ravichandran KS. Apoptosis and engulfment by bronchial epithelial cells. Implications for allergic airway inflammation. Ann Am Thorac Soc. 2014;11(Suppl 5):S259–S262. doi:10.1513/AnnalsATS.201405-200AW.
  • Chauss D, Brennan LA, Teng B, Kantorow M. Lens epithelial cells use phagocytosis as a mechanism to remove apoptotic cellular debris. Invest Opthalmol Vis Sci. 2014;55(13):3568.
  • Lee CS, Penberthy KK, Wheeler KM, et al. Boosting apoptotic cell clearance by colonic epithelial cells attenuates inflammation in vivo. Immunity. 2016;44(4):807–820. doi:10.1016/j.immuni.2016.02.005.
  • Park D, Tosello-Trampont A-C, Elliott MR, et al. BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module. Nature. 2007;450(7168):430–434. doi:10.1038/nature06329.
  • Han CZ, Juncadella IJ, Kinchen JM, et al. Macrophages redirect phagocytosis by non-professional phagocytes and influence inflammation. Nature. 2016;539(7630):570–574. doi:10.1038/nature20141.
  • Arango Duque G, Descoteaux A. Macrophages tell the non-professionals what to do. Dev Cell. 2016;39(6):633–635. doi:10.1016/j.devcel.2016.12.009.
  • Wu Y, Wu W, Wong WM, et al. Human gamma delta T cells: a lymphoid lineage cell capable of professional phagocytosis. J Immunol. 2009;183(9):5622–5629. doi:10.4049/jimmunol.0901772.
  • Zhu Q, Zhang M, Shi M, et al. Human B cells have an active phagocytic capability and undergo immune activation upon phagocytosis of Mycobacterium tuberculosis. Immunobiology. 2016;221(4):558–567. doi:10.1016/j.imbio.2015.12.003.
  • Martínez-Riaño A, Bovolenta ER, Mendoza P, et al. Antigen phagocytosis by B cells is required for a potent humoral response. EMBO Rep. 2018;19(9):e46016. doi:10.15252/embr.201846016.
  • Levine B, Mizushima N, Virgin HW. Autophagy in immunity and inflammation. Nature. 2011;469(7330):323–335. doi:10.1038/nature09782.
  • Matsuzawa-Ishimoto Y, Hwang S, Cadwell K. Autophagy and inflammation. Annu Rev Immunol. 2018;36(1):73–101. doi:10.1146/annurev-immunol-042617-053253.
  • Stuart LM, Ezekowitz RAB. Phagocytosis: elegant complexity. Immunity. 2005;22(5):539–550. doi:10.1016/j.immuni.2005.05.002.
  • Yuste J, Sen A, Truedsson L, et al. Impaired opsonization with c3b and phagocytosis of Streptococcus pneumoniae in sera from subjects with defects in the classical complement pathway. Infect Immun. 2008;76(8):3761–3770. doi:10.1128/IAI.00291-08.
  • Munoz LE, Peter C, Herrmann M, Wesselborg S, Lauber K. Scent of dying cells: the role of attraction signals in the clearance of apoptotic cells and its immunological consequences. Autoimmun Rev. 2010;9(6):425–430. doi:10.1016/j.autrev.2009.11.016.
  • Henson P, Bratton D. Recognition and Removal of Apoptotic Cells. In Russell D, Gordon S, editors. Phagocyte-Pathogen Interactions. Washington, DC: ASM Press; 2009. pp 341–365. doi:10.1128/9781555816650.ch21
  • Karaji N, Sattentau QJ. Efferocytosis of pathogen-infected cells. Front Immunol. 2017;8:1863. doi:10.3389/fimmu.2017.01863.
  • Elliott MR, Koster KM, Murphy PS. Efferocytosis signaling in the regulation of macrophage inflammatory responses. J Immunol. 2017;198(4):1387–1394. doi:10.4049/jimmunol.1601520.
  • Abdolmaleki F, Farahani N, Gheibi Hayat SM, et al. The role of efferocytosis in autoimmune diseases. Front Immunol. 2018;9:1645. doi:10.3389/fimmu.2018.01645.
  • Gavrilescu LC, Denkers EY. Apoptosis and the balance of homeostatic and pathologic responses to protozoan infection. Infect Immun. 2003;71(11):6109–6115. doi:10.1128/IAI.71.11.6109-6115.2003.
  • Giovannetti A, Pierdominici M, Di Iorio A, et al. Apoptosis in the homeostasis of the immune system and in human immune mediated diseases. Curr Pharm Des. 2008;14(3):253–268. doi:10.2174/138161208783413310.
  • Trahtemberg U, Mevorach D. Apoptotic cells induced signaling for immune homeostasis in macrophages and dendritic cells. Front Immunol. 2017;8:1356. doi:10.3389/fimmu.2017.01356.
  • Penberthy KK, Ravichandran KS. Apoptotic cell recognition receptors and scavenger receptors. Immunol Rev. 2016;269(1):44–59. doi:10.1111/imr.12376.
  • Das S, Owen KA, Ly KT, 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. 2011;108(5):2136–2141. doi:10.1073/pnas.1014775108.
  • Gregory CD. CD14-dependent clearance of apoptotic cells: relevance to the immune system. Curr Opin Immunol. 2000;12(1):27–34. doi:10.1016/S0952-7915(99)00047-3.
  • Gregory CD, Devitt A. The macrophage and the apoptotic cell: an innate immune interaction viewed simplistically? Immunology. 2004;113(1):1–14. doi:10.1111/j.1365-2567.2004.01959.x.
  • Arur S, Uche UE, Rezaul K, et al. Annexin I is an endogenous ligand that mediates apoptotic cell engulfment. Dev Cell. 2003;4(4):587–598. doi:10.1016/S1534-5807(03)00090-X.
  • Moffatt OD, Devitt A, Bell ED, Simmons DL, Gregory CD. Macrophage recognition of ICAM-3 on apoptotic leukocytes. J Immunol (Baltimore, Md.: 1950). 1999;162(11):6800–6810.
  • Torr EE, Gardner DH, Thomas L, et al. Apoptotic cell-derived ICAM-3 promotes both macrophage chemoattraction to and tethering of apoptotic cells. Cell Death Differ. 2012;19(4):671–679. doi:10.1038/cdd.2011.167.
  • Vandivier RW, Ogden CA, Fadok VA, et al. Role of surfactant proteins A, D, and C1q in the clearance of apoptotic cells in vivo and in vitro: calreticulin and CD91 as a common collectin receptor complex. J Immunol. 2002;169(7):3978–3986. doi:10.4049/jimmunol.169.7.3978.
  • Fond AM, Ravichandran KS. Clearance of dying cells by phagocytes: mechanisms and implications for disease pathogenesis. Adv Exp Med Biol. 2016;930:25–49. doi:10.1007/978-3-319-39406-0_2.
  • Park S-Y, Kim I-S. Engulfment signals and the phagocytic machinery for apoptotic cell clearance. Exp Mol Med. 2017;49(5):e331. doi:10.1038/emm.2017.52.
  • Truman LA, Ford CA, Pasikowska M, et al. CX3CL1/fractalkine is released from apoptotic lymphocytes to stimulate macrophage chemotaxis. Blood. 2008;112(13):5026–5036. doi:10.1182/blood-2008-06-162404.
  • Sokolowski JD, Chabanon-Hicks CN, Han CZ, Heffron DS, Mandell JW. Fractalkine is a “find-me” signal released by neurons undergoing ethanol-induced apoptosis. Front Cell Neurosci. 2014;8:360. doi:10.3389/fncel.2014.00360.
  • Chekeni FB, Ravichandran KS. The role of nucleotides in apoptotic cell clearance: implications for disease pathogenesis. J Mol Med. 2011;89(1):13–22. doi:10.1007/s00109-010-0673-7.
  • Yang LV, Radu CG, Wang L, Riedinger M, Witte ON. Gi-independent macrophage chemotaxis to lysophosphatidylcholine via the immunoregulatory GPCR G2A. Blood. 2005;105(3):1127–1134. doi:10.1182/blood-2004-05-1916.
  • Kern K, Schäfer SMG, Cohnen J, et al. The G2A receptor controls polarization of macrophage by determining their localization within the inflamed tissue. Front Immunol. 2018;9:2261. doi:10.3389/fimmu.2018.02261.
  • Thome AD, Standaert DG, Harms AS. Fractalkine signaling regulates the inflammatory response in an α-synuclein model of Parkinson disease. PLoS One. 2015;10(10):e0140566. doi:10.1371/journal.pone.0140566.
  • Gevrey J-C, Isaac BM, Cox D. Syk is required for monocyte/macrophage chemotaxis to CX3CL1 (fractalkine). J Immunol. 2005;175(6):3737–3745. doi:10.4049/jimmunol.175.6.3737.
  • Morioka S, Maueröder C, Ravichandran KS. Living on the edge: efferocytosis at the interface of homeostasis and pathology. Immunity. 2019;50(5):1149–1162. doi:10.1016/j.immuni.2019.04.018.
  • Nagata S, Hanayama R, Kawane K. Autoimmunity and the clearance of dead cells. Cell. 2010;140(5):619–630. doi:10.1016/j.cell.2010.02.014.
  • Verhoven B, Schlegel RA, Williamson P. Mechanisms of phosphatidylserine exposure, a phagocyte recognition signal, on apoptotic T lymphocytes. J Exp Med. 1995;182(5):1597–1601. doi:10.1084/jem.182.5.1597.
  • Bratton DL, Fadok VA, Richter DA, Kailey JM, Guthrie LA, Henson PM. Appearance of phosphatidylserine on apoptotic cells requires calcium-mediated nonspecific flip-flop and is enhanced by loss of the aminophospholipid translocase. J Biol Chem. 1997;272(42):26159–26165. doi:10.1074/jbc.272.42.26159.
  • Suzuki J, Denning DP, Imanishi E, Horvitz HR, Nagata S. Xk-related protein 8 and CED-8 promote phosphatidylserine exposure in apoptotic cells. Science. 2013;341(6144):403–406. doi:10.1126/science.1236758.
  • Kobayashi N, Karisola P, Pena-Cruz V, et al. TIM-1 and TIM-4 glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells. Immunity. 2007;27(6):927–940. doi:10.1016/j.immuni.2007.11.011.
  • Freeman GJ, Casasnovas JM, Umetsu DT, DeKruyff RH. TIM genes: a family of cell surface phosphatidylserine receptors that regulate innate and adaptive immunity. Immunol Rev. 2010;235(1):172–189. doi:10.1111/j.0105-2896.2010.00903.x.
  • Park SY, Jung MY, Kim HJ, et al. Rapid cell corpse clearance by stabilin-2, a membrane phosphatidylserine receptor. Cell Death Differ. 2008;15(1):192–201. doi:10.1038/sj.cdd.4402242.
  • Kourtzelis I, Li X, Mitroulis I, et al. DEL-1 promotes macrophage efferocytosis and clearance of inflammation. Nat Immunol. 2019;20(1):40–49. doi:10.1038/s41590-018-0249-1.
  • Myers KV, Amend SR, Pienta KJ. Targeting Tyro3, Axl and MerTK (TAM receptors): implications for macrophages in the tumor microenvironment. Mol Cancer. 2019;18(1):94. doi:10.1186/s12943-019-1022-2.
  • Borisenko GG, Matsura T, Liu SX, et al. Macrophage recognition of externalized phosphatidylserine and phagocytosis of apoptotic Jurkat cells–existence of a threshold. Arch Biochem Biophys. 2003;413(1):41–52. doi:10.1016/S0003-9861(03)00083-3.
  • Park SY, Jung MY, Lee SJ, et al. Stabilin-1 mediates phosphatidylserine-dependent clearance of cell corpses in alternatively activated macrophages. J Cell Sci. 2009;122(18):3365–3373. doi:10.1242/jcs.049569.
  • Park SY, Kim SY, Jung MY, Bae DJ, Kim IS. Epidermal growth factor-like domain repeat of stabilin-2 recognizes phosphatidylserine during cell corpse clearance. Mol Cell Biol. 2008;28(17):5288–5298. doi:10.1128/MCB.01993-07.
  • Kzhyshkowska J, Gratchev A, Goerdt S. Stabilin-1, a homeostatic scavenger receptor with multiple functions. J Cellular Mol Med. 2006;10(3):635–649. doi:10.1111/j.1582-4934.2006.tb00425.x.
  • Anderson HA, Maylock CA, Williams JA, Paweletz CP, Shu H, Shacter E. Serum-derived protein S binds to phosphatidylserine and stimulates the phagocytosis of apoptotic cells. Nat Immunol. 2003;4(1):87–91. doi:10.1038/ni871.
  • Hanayama R, Tanaka M, Miwa K, Shinohara A, Iwamatsu A, Nagata S. Identification of a factor that links apoptotic cells to phagocytes. Nature. 2002;417(6885):182–187. doi:10.1038/417182a.
  • He YW, Li H, Zhang J, et al. The extracellular matrix protein mindin is a pattern-recognition molecule for microbial pathogens. Nat Immunol. 2004;5(1):88–97. doi:10.1038/ni1021.
  • Akakura S, Singh S, Spataro M, 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. 2004;292(2):403–416. doi:10.1016/j.yexcr.2003.09.011.
  • Wu Y, Singh S, Georgescu MM, Birge RB. A role for Mer tyrosine kinase in alphavbeta5 integrin-mediated phagocytosis of apoptotic cells. J Cell Sci. 2005;118(3):539–553. doi:10.1242/jcs.01632.
  • Aziz M, Jacob A, Matsuda A, Wang P. Review: milk fat globule-EGF factor 8 expression, function and plausible signal transduction in resolving inflammation. Apoptosis. 2011;16(11):1077–1086. doi:10.1007/s10495-011-0630-0.
  • Yamaguchi H, Takagi J, Miyamae T, et al. Milk fat globule EGF factor 8 in the serum of human patients of systemic lupus erythematosus. J Leukocyte Biol. 2008;83(5):1300–1307. doi:10.1189/jlb.1107730.
  • Yamaguchi H, Fujimoto T, Nakamura S, et al. Aberrant splicing of the milk fat globule-EGF factor 8 (MFG-E8) gene in human systemic lupus erythematosus. Eur J Immunol. 2010;40(6):1778–1785. doi:10.1002/eji.200940096.
  • Hu CY, Wu CS, Tsai HF, Chang SK, Tsai WI, Hsu PN. Genetic polymorphism in milk fat globule-EGF factor 8 (MFG-E8) is associated with systemic lupus erythematosus in human. Lupus. 2009;18(8):676–681. doi:10.1177/0961203309103027.
  • Hanayama R, Miyasaka K, Nakaya M, Nagata S. MFG-E8-dependent clearance of apoptotic cells, and autoimmunity caused by its failure. Curr Dir Autoimmun. 2006;9:162–172. doi:10.1159/000090780.
  • Hanayama R, Tanaka M, Miyasaka K, et al. Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice. Science. 2004;304(5674):1147–1150. doi:10.1126/science.1094359.
  • Yamamoto N, Yamaguchi H, Ohmura K, et al. Serum milk fat globule epidermal growth factor 8 elevation may subdivide systemic lupus erythematosus into two pathophysiologically distinct subsets. Lupus. 2014;23(4):386–394. doi:10.1177/0961203314523870.
  • Kishi C, Motegi SI, Ishikawa O. Elevated serum MFG-E8 level is possibly associated with the presence of high-intensity cerebral lesions on magnetic resonance imaging in patients with systemic lupus erythematosus. J Dermatol. 2017;44(7):783–788. doi:10.1111/1346-8138.13791.
  • Li BZ, Zhang HY, Pan HF, Ye DQ. Identification of MFG-E8 as a novel therapeutic target for diseases. Expert Opin Ther Targets. 2013;17(11):1275–1285. doi:10.1517/14728222.2013.829455.
  • Huang W, Wu J, Yang H, et al. Milk fat globule-EGF factor 8 suppresses the aberrant immune response of systemic lupus erythematosus-derived neutrophils and associated tissue damage. Cell Death Differ. 2017;24(2):263–275. doi:10.1038/cdd.2016.115.
  • Lauber K, Keppeler H, Munoz LE, et al. Milk fat globule-EGF factor 8 mediates the enhancement of apoptotic cell clearance by glucocorticoids. Cell Death Differ. 2013;20(9):1230–1240. doi:10.1038/cdd.2013.82.
  • McColl A, Bournazos S, Franz S, et al. Glucocorticoids induce protein S-dependent phagocytosis of apoptotic neutrophils by human macrophages. J Immunol. 2009;183(3):2167–2175. doi:10.4049/jimmunol.0803503.
  • Hodrea J, Majai G, Doro Z, et al. The glucocorticoid dexamethasone programs human dendritic cells for enhanced phagocytosis of apoptotic neutrophils and inflammatory response. J Leukocyte Biol. 2012;91(1):127–136. doi:10.1189/jlb.0511243.
  • Uehara H, Shacter E. Auto-oxidation and oligomerization of protein S on the apoptotic cell surface is required for Mer tyrosine kinase-mediated phagocytosis of apoptotic cells. J Immunol. 2008;180(4):2522–2530. doi:10.4049/jimmunol.180.4.2522.
  • Hafizi S, Dahlback B. Gas6 and protein S. Vitamin K-dependent ligands for the Axl receptor tyrosine kinase subfamily. FEBS J. 2006;273(23):5231–5244.
  • Stitt TN, Conn G, Gore M, et al. The anticoagulation factor protein S and its relative, Gas6, are ligands for the Tyro 3/Axl family of receptor tyrosine kinases. Cell. 1995;80(4):661–670. doi:10.1016/0092-8674(95)90520-0.
  • Rothlin CV, Lemke G. TAM receptor signaling and autoimmune disease. Curr Opin Immunol. 2010;22(6):740–746. doi:10.1016/j.coi.2010.10.001.
  • Rothlin CV, Ghosh S, Zuniga EI, Oldstone MB, Lemke G. TAM receptors are pleiotropic inhibitors of the innate immune response. Cell. 2007;131(6):1124–1136. doi:10.1016/j.cell.2007.10.034.
  • Rothlin CV, Carrera-Silva EA, Bosurgi L, Ghosh S. TAM receptor signaling in immune homeostasis. Annu Rev Immunol. 2015;33(1):355–391. doi:10.1146/annurev-immunol-032414-112103.
  • Lumbroso D, Soboh S, Maimon A, Schif-Zuck S, Ariel A, Burstyn-Cohen T. Macrophage-derived protein S facilitates apoptotic polymorphonuclear cell clearance by resolution phase macrophages and supports their reprogramming. Front Immunol. 2018;9:358. doi:10.3389/fimmu.2018.00358.
  • Proto JD, Doran AC, Gusarova G, et al. Regulatory T cells promote macrophage efferocytosis during inflammation resolution. Immunity. 2018;49(4):666–677.e6. doi:10.1016/j.immuni.2018.07.015.
  • Salina AC, Souza TP, Serezani CH, Medeiros AI. Efferocytosis-induced prostaglandin E2 production impairs alveolar macrophage effector functions during Streptococcus pneumoniae infection. Innate Immun. 2017;23(3):219–227. doi:10.1177/1753425916684934.
  • Esmann L, Idel C, Sarkar A, et al. Phagocytosis of apoptotic cells by neutrophil granulocytes: diminished proinflammatory neutrophil functions in the presence of apoptotic cells. J Immun. 2010;184(1):391–400. doi:10.4049/jimmunol.0900564.
  • Marwick JA, Mills R, Kay O, et al. Neutrophils induce macrophage anti-inflammatory reprogramming by suppressing NF-κB activation. Cell Death Dis. 2018;9(6):665. doi:10.1038/s41419-018-0710-y.
  • Murphy JE, Tedbury PR, Homer-Vanniasinkam S, Walker JH, Ponnambalam S. Biochemistry and cell biology of mammalian scavenger receptors. Atherosclerosis. 2005;182(1):1–15. doi:10.1016/j.atherosclerosis.2005.03.036.
  • Peiser L, Gordon S. The function of scavenger receptors expressed by macrophages and their role in the regulation of inflammation. Microbes Infect. 2001;3(2):149–159. doi:10.1016/S1286-4579(00)01362-9.
  • Goldstein JL, Ho YK, Basu SK, Brown MS. Binding site on macrophages that mediates uptake and degradation of acetylated low density lipoprotein, producing massive cholesterol deposition. Proc Natl Acad Sci USA. 1979;76(1):333–337. doi:10.1073/pnas.76.1.333.
  • Fogelman AM, Haberland ME, Seager J, Hokom M, Edwards PA. Factors regulating the activities of the low density lipoprotein receptor and the scavenger receptor on human monocyte-macrophages. J Lipid Res. 1981;22(7):1131–1141.
  • Patten DA, Shetty S. More than just a removal service: scavenger receptors in leukocyte trafficking. Front Immunol. 2018;9:2904. doi:10.3389/fimmu.2018.02904.
  • Canton J, Neculai D, Grinstein S. Scavenger receptors in homeostasis and immunity. Nat Rev Immunol. 2013;13(9):621–634. doi:10.1038/nri3515.
  • Dunne DW, Resnick D, Greenberg J, Krieger M, Joiner KA. The type I macrophage scavenger receptor binds to gram-positive bacteria and recognizes lipoteichoic acid. Proc Natl Acad Sci USA. 1994;91(5):1863–1867. doi:10.1073/pnas.91.5.1863.
  • Fadok VA, Warner ML, Bratton DL, Henson PM. CD36 is required for phagocytosis of apoptotic cells by human macrophages that use either a phosphatidylserine receptor or the vitronectin receptor (alpha v beta 3). J Immunol (Baltimore, Md.: 1950). 1998;161(11):6250–6257.
  • Adachi H, Tsujimoto M. Endothelial scavenger receptors. Prog Lipid Res. 2006;45(5):379–404. doi:10.1016/j.plipres.2006.03.002.
  • Shiratsuchi A, Kawasaki Y, Ikemoto M, Arai H, Nakanishi Y. Role of class b scavenger receptor type I in phagocytosis of apoptotic rat spermatogenic cells by Sertoli cells. J Biol Chem. 1999;274(9):5901–5908. doi:10.1074/jbc.274.9.5901.
  • PrabhuDas MR, Baldwin CL, Bollyky PL, et al. A consensus definitive classification of scavenger receptors and their roles in health and disease. J Immun. 2017;198(10):3775–3789. doi:10.4049/jimmunol.1700373.
  • Gazi U, Martinez-Pomares L. Influence of the mannose receptor in host immune responses. Immunobiology. 2009;214(7):554–561. doi:10.1016/j.imbio.2008.11.004.
  • Herre J, Marshall AS, Caron E, et al. Dectin-1 uses novel mechanisms for yeast phagocytosis in macrophages. Blood. 2004;104(13):4038–4045. doi:10.1182/blood-2004-03-1140.
  • Devitt A, Pierce S, Oldreive C, Shingler WH, Gregory CD. CD14-dependent clearance of apoptotic cells by human macrophages: the role of phosphatidylserine. Cell Death Differ. 2003;10(3):371–382. doi:10.1038/sj.cdd.4401168.
  • Devitt A, Moffatt OD, Raykundalia C, Capra JD, Simmons DL, Gregory CD. Human CD14 mediates recognition and phagocytosis of apoptotic cells. Nature. 1998;392(6675):505–509. doi:10.1038/33169.
  • Areschoug T, Gordon S. Scavenger receptors: role in innate immunity and microbial pathogenesis. Cell Microbiol. 2009;11(8):1160–1169. doi:10.1111/j.1462-5822.2009.01326.x.
  • Blander JM, Medzhitov R. Regulation of phagosome maturation by signals from toll-like receptors. Science. 2004;304(5673):1014–1018. doi:10.1126/science.1096158.
  • Doyle SE, O'Connell RM, Miranda GA, et al. Toll-like receptors induce a phagocytic gene program through p38. J Exp Med. 2004;199(1):81–90. doi:10.1084/jem.20031237.
  • Underhill DM, Ozinsky A, Hajjar AM, et al. The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens. Nature. 1999;401(6755):811–815. doi:10.1038/44605.
  • Ramirez-Ortiz ZG, Pendergraft WF III, Prasad A, et al. The scavenger receptor SCARF1 mediates the clearance of apoptotic cells and prevents autoimmunity. Nat Immunol. 2013;14(9):917–926. doi:10.1038/ni.2670.
  • Todt JC, Hu B, Curtis JL. The scavenger receptor SR-A I/II (CD204) signals via the receptor tyrosine kinase Mertk during apoptotic cell uptake by murine macrophages. J Leukocyte Biol. 2008;84(2):510–518. doi:10.1189/jlb.0307135.
  • Hamasaki S, Kobori T, Yamazaki Y, et al. Effects of scavenger receptors-1 class A stimulation on macrophage morphology and highly modified advanced glycation end product-protein phagocytosis. Sci Rep. 2018;8(1):5901. doi:10.1038/s41598-018-24325-y.
  • Indik ZK, Hunter S, Huang MM, et al. The high affinity Fc gamma receptor (CD64) induces phagocytosis in the absence of its cytoplasmic domain: the gamma subunit of Fc gamma RIIIA imparts phagocytic function to Fc gamma RI. Exp Hematol. 1994;22(7):599–606.
  • Hawley KL, Cruz AR, Benjamin SJ, et al. IFNγ enhances CD64-potentiated phagocytosis of treponema pallidum opsonized with human syphilitic serum by human macrophages. Front Immunol. 2017;8:1227. doi:10.3389/fimmu.2017.01227.
  • Vaillancourt M, Levasseur S, Tremblay ML, Marois L, Rollet-Labelle E, Naccache PH. The Src homology 2-containing inositol 5-phosphatase 1 (SHIP1) is involved in CD32a signaling in human neutrophils. Cell Signal. 2006;18(11):2022–2032. doi:10.1016/j.cellsig.2006.03.012.
  • Groves E, Dart AE, Covarelli V, Caron E. Molecular mechanisms of phagocytic uptake in mammalian cells, Cellular and molecular life sciences. Cell Mol Life Sci. 2008;65(13):1957–1976. doi:10.1007/s00018-008-7578-4.
  • Rosales C, Uribe-Querol E. Phagocytosis: a fundamental process in immunity. Biomed Res Int. 2017;2017:1–18. doi:10.1155/2017/9042851.
  • de Tymowski C, Heming N, Correia MDT, et al. CD89 is a potent innate receptor for bacteria and mediates host protection from sepsis. Cell Reports. 2019;27(3):762–775.e5. doi:10.1016/j.celrep.2019.03.062.
  • Lukacsi S, Nagy-Balo Z, Erdei A, Sandor N, Bajtay Z. The role of CR3 (CD11b/CD18) and CR4 (CD11c/CD18) in complement-mediated phagocytosis and podosome formation by human phagocytes. Immunol Lett. 2017;189:64–72. doi:10.1016/j.imlet.2017.05.014.
  • Helmy KY, Katschke KJ Jr, Gorgani NN, et al. CRIg: a macrophage complement receptor required for phagocytosis of circulating pathogens. Cell. 2006;124(5):915–927. doi:10.1016/j.cell.2005.12.039.
  • Aderem A, Underhill DM. Mechanisms of phagocytosis in macrophages. Annu Rev Immunol. 1999;17(1):593–623. doi:10.1146/annurev.immunol.17.1.593.
  • Alva-Murillo N, López-Meza JE, Ochoa-Zarzosa A. Nonprofessional phagocytic cell receptors involved in Staphylococcus aureus internalization. Biomed Res Int. 2014;2014:538546. doi:10.1155/2014/538546.
  • Varki A. Natural ligands for CD33-related Siglecs? Glycobiology. 2009;19(8):810–812. doi:10.1093/glycob/cwp063.
  • Zhao L. CD33 in Alzheimer’s disease – biology, pathogenesis, and therapeutics: a mini-review. Gerontology. 2019;65(4):323–331. doi:10.1159/000492596.
  • Dupuy AG, Caron E. Integrin-dependent phagocytosis – spreading from microadhesion to new concepts. J Cell Sci. 2008;121(11):1773–1783. doi:10.1242/jcs.018036.
  • Kagan VE, Borisenko GG, Serinkan BF, et al. Appetizing rancidity of apoptotic cells for macrophages: oxidation, externalization, and recognition of phosphatidylserine. Am J Physiol Lung Cell Mol Physiol. 2003;285(1):L1–L17. doi:10.1152/ajplung.00365.2002.
  • Greenberg ME, Sun M, Zhang R, Febbraio M, Silverstein R, Hazen SL. Oxidized phosphatidylserine-CD36 interactions play an essential role in macrophage-dependent phagocytosis of apoptotic cells. J Exp Med. 2006;203(12):2613–2625. doi:10.1084/jem.20060370.
  • Woo M-S, Yang J, Beltran C, Cho S. Cell-surface CD36 in monocyte/macrophage contributes to phagocytosis during the resolution phase of ischemic stroke in mice. J Biol Chem. 2016;291(45):23654–23661. doi:10.1074/jbc.M116.750018.
  • Dehn S, Thorp EB. Myeloid receptor CD36 is required for early phagocytosis of myocardial infarcts and induction of Nr4a1-dependent mechanisms of cardiac repair. FASEB J. 2018;32(1):254–264. doi:10.1096/fj.201700450R.
  • Park YM. CD36, a scavenger receptor implicated in atherosclerosis. Exp Mol Med. 2014;46:e99. doi:10.1038/emm.2014.38.
  • Olonisakin TF, Li H, Xiong Z, et al. CD36 provides host protection against Klebsiella pneumoniae intrapulmonary infection by enhancing lipopolysaccharide responsiveness and macrophage phagocytosis. J Infect Dis. 2016;214(12):1865–1875. doi:10.1093/infdis/jiw451.
  • Patel SN, Serghides L, Smith TG, et al. CD36 mediates the phagocytosis of Plasmodium falciparum–infected erythrocytes by rodent macrophages. J Infect Dis. 2004;189(2):204–213. doi:10.1086/380764.
  • Kristof E, Zahuczky G, Katona K, Doro Z, Nagy E, Fesus L. Novel role of ICAM3 and LFA-1 in the clearance of apoptotic neutrophils by human macrophages. Apoptosis. 2013;18(10):1235–1251. doi:10.1007/s10495-013-0873-z.
  • Guillou A, Troha K, Wang H, Franc NC, Buchon N. The Drosophila CD36 homologue croquemort is required to maintain immune and gut homeostasis during development and aging. PLoS Pathog. 2016;12(10):e1005961. doi:10.1371/journal.ppat.1005961.
  • Franc NC, Heitzler P, Ezekowitz RA, White K. Requirement for croquemort in phagocytosis of apoptotic cells in Drosophila. Science. 1999;284(5422):1991–1994. doi:10.1126/science.284.5422.1991.
  • Franc NC, Dimarcq JL, Lagueux M, Hoffmann J, Ezekowitz RA. Croquemort, a novel Drosophila hemocyte/macrophage receptor that recognizes apoptotic cells. Immunity. 1996;4(5):431–443. doi:10.1016/S1074-7613(00)80410-0.
  • Murshid A, Borges TJ, Calderwood SK. Emerging roles for scavenger receptor SREC-I in immunity. Cytokine. 2015;75(2):256–260. doi:10.1016/j.cyto.2015.02.009.
  • Murshid A, Borges TJ, Lang BJ, Calderwood SK. The scavenger receptor SREC-I cooperates with toll-like receptors to trigger inflammatory innate immune responses. Front Immunol. 2016;7:226. doi:10.3389/fimmu.2016.00226.
  • Murshid A, Gong J, Ahmad R, Borges TJ, Calderwood SK. Scavenger receptor SREC-I promotes double stranded RNA-mediated TLR3 activation in human monocytes. Immunobiology. 2015;220(6):823–832. doi:10.1016/j.imbio.2014.12.011.
  • Murshid A, Gong J, Prince T, Borges TJ, Calderwood SK. Scavenger receptor SREC-I mediated entry of TLR4 into lipid microdomains and triggered inflammatory cytokine release in RAW 264.7 cells upon LPS activation. PLoS One. 2015;10(4):e0122529. doi:10.1371/journal.pone.0122529.
  • Uchida Y, Ke B, Freitas MC, et al. The emerging role of T cell immunoglobulin mucin-1 in the mechanism of liver ischemia and reperfusion injury in the mouse. Hepatology (Baltimore, Md.). 2010;51(4):1363–1372. doi:10.1002/hep.23442.
  • Ji H, Liu Y, Zhang Y, et al. T-cell immunoglobulin and mucin domain 4 (TIM-4) signaling in innate immune-mediated liver ischemia-reperfusion injury. Hepatology (Baltimore, Md.). 2014;60(6):2052–2064. doi:10.1002/hep.27334.
  • Schiff DE, Kline L, Soldau K, et al. Phagocytosis of gram-negative bacteria by a unique CD14-dependent mechanism. J Leukoc Biol. 1997;62(6):786–794. doi:10.1002/jlb.62.6.786.
  • Lingnau M, Hoflich C, Volk HD, Sabat R, Docke WD. Interleukin-10 enhances the CD14-dependent phagocytosis of bacteria and apoptotic cells by human monocytes. Hum Immunol. 2007;68(9):730–738. doi:10.1016/j.humimm.2007.06.004.
  • Liu Y, Walter S, Stagi M, et al. LPS receptor (CD14): a receptor for phagocytosis of Alzheimer’s amyloid peptide. Brain. 2005;128(8):1778–1789. doi:10.1093/brain/awh531.
  • Allavena P, Chieppa M, Monti P, Piemonti L. From pattern recognition receptor to regulator of homeostasis: the double-faced macrophage mannose receptor. Crit Rev Immunol. 2004;24(3):179–192. doi:10.1615/CritRevImmunol.v24.i3.20.
  • Xu X, Jin T. ELMO proteins transduce G protein-coupled receptor signal to control reorganization of actin cytoskeleton in chemotaxis of eukaryotic cells. Small GTPases. 2019;10(4):271–279. doi:10.1080/21541248.2017.1318816.
  • Lu J, Mold C, Du Clos TW, Sun PD. Pentraxins and Fc receptor-mediated immune responses. Front Immunol. 2018;9:2607. doi:10.3389/fimmu.2018.02607.
  • Lu J, Marjon KD, Mold C, Du Clos TW, Sun PD. Pentraxins and Fc receptors. Immunol Rev. 2012;250(1):230–238. doi:10.1111/j.1600-065X.2012.01162.x.
  • Cabec VL, Carréno S, Moisand A, Bordier C, Maridonneau-Parini I. Complement receptor 3 (CD11b/CD18) mediates type I and type II phagocytosis during nonopsonic and opsonic phagocytosis, respectively. J Immunol. 2002;169(4):2003–2009. doi:10.4049/jimmunol.169.4.2003.
  • Flesch BK, Voge K, Henrichs T, Neppert J. Fcgamma receptor-mediated immune phagocytosis depends on the class of FcgammaR and on the immunoglobulin-coated target cell. Vox Sang. 2001;81(2):128–133. doi:10.1046/j.1423-0410.2001.00081.x.
  • Goodridge HS, Underhill DM, Touret N. Mechanisms of Fc receptor and dectin-1 activation for phagocytosis. Traffic (Copenhagen, Denmark). 2012;13(8):1062–1071. doi:10.1111/j.1600-0854.2012.01382.x.
  • Goodridge HS, Simmons RM, Underhill DM. Dectin-1 stimulation by Candida albicans yeast or zymosan triggers NFAT activation in macrophages and dendritic cells. J Immunol. 2007;178(5):3107–3115. doi:10.4049/jimmunol.178.5.3107.
  • Kingeter LM, Lin X. C-type lectin receptor-induced NF-kappaB activation in innate immune and inflammatory responses. Cell Mol Immunol. 2012;9(2):105–112. doi:10.1038/cmi.2011.58.
  • Reid DM, Gow NA, Brown GD. Pattern recognition: recent insights from Dectin-1. Curr Opin Immunol. 2009;21(1):30–37. doi:10.1016/j.coi.2009.01.003.
  • Araki N, Johnson MT, Swanson JA. A role for phosphoinositide 3-kinase in the completion of macropinocytosis and phagocytosis by macrophages. J Cell Biol. 1996;135(5):1249–1260. doi:10.1083/jcb.135.5.1249.
  • Dewitt S, Tian W, Hallett MB. Localised PtdIns(3,4,5)P3 or PtdIns(3,4)P2 at the phagocytic cup is required for both phagosome closure and Ca2+ signalling in HL60 neutrophils. J Cell Sci. 2006;119(3):443–451. doi:10.1242/jcs.02756.
  • Gu H, Botelho RJ, Yu M, Grinstein S, Neel BG. Critical role for scaffolding adapter Gab2 in Fc gamma R-mediated phagocytosis. J Cell Biol. 2003;161(6):1151–1161. doi:10.1083/jcb.200212158.
  • Nigorikawa K, Hazeki K, Sasaki J, et al. Inositol polyphosphate-4-phosphatase type I negatively regulates phagocytosis via dephosphorylation of phagosomal PtdIns(3,4)P2. PLoS One. 2015;10(11):e0142091. doi:10.1371/journal.pone.0142091.
  • Horan KA, Watanabe K, Kong AM, et al. Regulation of FcgammaR-stimulated phagocytosis by the 72-kDa inositol polyphosphate 5-phosphatase: SHIP1, but not the 72-kDa 5-phosphatase, regulates complement receptor 3 mediated phagocytosis by differential recruitment of these 5-phosphatases to the phagocytic cup. Blood. 2007;110(13):4480–4491. doi:10.1182/blood-2007-02-073874.
  • Kamen LA, Levinsohn J, Cadwallader A, Tridandapani S, Swanson JA. SHIP-1 increases early oxidative burst and regulates phagosome maturation in macrophages. J Immunol. 2008;180(11):7497–7505. doi:10.4049/jimmunol.180.11.7497.
  • Wang AV, Scholl PR, Geha RS. Physical and functional association of the high affinity immunoglobulin G receptor (Fc gamma RI) with the kinases Hck and Lyn. J Exp Med. 1994;180(3):1165–1170. doi:10.1084/jem.180.3.1165.
  • Hamada F, Aoki M, Akiyama T, Toyoshima K. Association of immunoglobulin G Fc receptor II with Src-like protein-tyrosine kinase Fgr in neutrophils. Proc Natl Acad Sci USA. 1993;90(13):6305–6309. doi:10.1073/pnas.90.13.6305.
  • Fitzer-Attas CJ, Lowry M, Crowley MT, et al. Fcgamma receptor-mediated phagocytosis in macrophages lacking the Src family tyrosine kinases Hck, Fgr, and Lyn. J Exp Med. 2000;191(4):669–682. doi:10.1084/jem.191.4.669.
  • Nishio M, Watanabe K, Sasaki J, et al. Control of cell polarity and motility by the PtdIns(3,4,5)P3 phosphatase SHIP1. Nat Cell Biol. 2007;9(1):36–44. doi:10.1038/ncb1515.
  • Ai J, Maturu A, Johnson W, Wang Y, Marsh CB, Tridandapani S. The inositol phosphatase SHIP-2 down-regulates FcgammaR-mediated phagocytosis in murine macrophages independently of SHIP-1. Blood. 2006;107(2):813–820. doi:10.1182/blood-2005-05-1841.
  • Crowley MT, Costello PS, Fitzer-Attas CJ, et al. A critical role for Syk in signal transduction and phagocytosis mediated by Fcgamma receptors on macrophages. J Exp Med. 1997;186(7):1027–1039. doi:10.1084/jem.186.7.1027.
  • Kiefer F, Brumell J, Al-Alawi N, et al. The Syk protein tyrosine kinase is essential for Fcgamma receptor signaling in macrophages and neutrophils. Mol Cell Biol. 1998;18(7):4209–4220. doi:10.1128/MCB.18.7.4209.
  • Nagelkerke SQ, Dekkers G, Kustiawan I, et al. Inhibition of FcγR-mediated phagocytosis by IVIg is independent of IgG-Fc sialylation and FcγRIIb in human macrophages. Blood. 2014;124(25):3709–3718. doi:10.1182/blood-2014-05-576835.
  • Freeman SA, Grinstein S. Phagocytosis: receptors, signal integration, and the cytoskeleton. Immunol Rev. 2014;262(1):193–215. doi:10.1111/imr.12212.
  • Shin DM, Yang CS, Yuk JM, et al. Mycobacterium abscessus activates the macrophage innate immune response via a physical and functional interaction between TLR2 and dectin-1. Cell Microbiol. 2008;10(8):1608–1621. doi:10.1111/j.1462-5822.2008.01151.x.
  • Rogers NC, Slack EC, Edwards AD, et al. Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins. Immunity. 2005;22(4):507–517. doi:10.1016/j.immuni.2005.03.004.
  • Goodridge HS, Reyes CN, Becker CA, et al. Activation of the innate immune receptor Dectin-1 upon formation of a ‘phagocytic synapse. Nature. 2011;472(7344):471–475. doi:10.1038/nature10071.
  • Haider M, Dambuza IM, Asamaphan P, et al. The pattern recognition receptors dectin-2, mincle, and FcRγ impact the dynamics of phagocytosis of Candida, Saccharomyces, Malassezia, and Mucor species. PLoS One. 2019;14(8):e0220867. doi:10.1371/journal.pone.0220867.
  • Vidya MK, Kumar VG, Sejian V, Bagath M, Krishnan G, Bhatta R. Toll-like receptors: significance, ligands, signaling pathways, and functions in mammals. Int Rev Immunol. 2018;37(1):20–36. doi:10.1080/08830185.2017.1380200.
  • Kumar V. Toll-like receptors in immunity and inflammatory diseases: past, present, and future. Int Immunopharmacol. 2018;59:391–412.
  • Kobayashi M, Saitoh S, Tanimura N, et al. Regulatory roles for MD-2 and TLR4 in ligand-induced receptor clustering. J Immunol. 2006;176(10):6211–6218. doi:10.4049/jimmunol.176.10.6211.
  • Kawasaki T, Kawai T. Toll-like receptor signaling pathways. Front Immunol. 2014;5:461–461. doi:10.3389/fimmu.2014.00461.
  • Fiebich BL, Batista CRA, Saliba SW, Yousif NM, de Oliveira ACP. Role of microglia TLRs in neurodegeneration. Front Cell Neurosci. 2018;12:329. doi:10.3389/fncel.2018.00329.
  • Kumar V. Toll-like receptors in the pathogenesis of neuroinflammation. J Neuroimmunol. 2019;332:16–30. doi:10.1016/j.jneuroim.2019.03.012.
  • Nie L, Cai S-Y, Shao J-Z, Chen J. Toll-like receptors, associated biological roles, and signaling networks in non-mammals. Front Immunol. 2018;9:1523. doi:10.3389/fimmu.2018.01523.
  • Yates RM, Russell DG. Phagosome maturation proceeds independently of stimulation of toll-like receptors 2 and 4. Immunity. 2005;23(4):409–417. doi:10.1016/j.immuni.2005.09.007.
  • Sjoelund V, Smelkinson M, Nita-Lazar A. Phosphoproteome profiling of the macrophage response to different toll-like receptor ligands identifies differences in global phosphorylation dynamics. J Proteome Res. 2014;13(11):5185–5197. doi:10.1021/pr5002466.
  • Yan M, Collins RF, Grinstein S, Trimble WS. Coronin-1 function is required for phagosome formation. Mol Biol Cell. 2005;16(7):3077–3087. doi:10.1091/mbc.e04-11-0989.
  • Oku T, Kaneko Y, Murofushi K, Seyama Y, Toyoshima S, Tsuji T. Phorbol ester-dependent phosphorylation regulates the association of p57/coronin-1 with the actin cytoskeleton. J Biol Chem. 2008;283(43):28918–28925. doi:10.1074/jbc.M709990200.
  • Kong L, Ge BX. MyD88-independent activation of a novel actin-Cdc42/Rac pathway is required for Toll-like receptor-stimulated phagocytosis. Cell Res. 2008;18(7):745–755. doi:10.1038/cr.2008.65.
  • Tomasevic N, Jia Z, Russell A, et al. Differential regulation of WASP and N-WASP by Cdc42, Rac1, Nck, and PI(4,5)P2. Biochemistry. 2007;46(11):3494–3502. doi:10.1021/bi062152y.
  • Pollard TD, Beltzner CC. Structure and function of the Arp2/3 complex. Curr Opin Struct Biol. 2002;12(6):768–774. doi:10.1016/S0959-440X(02)00396-2.
  • Dart AE, Donnelly SK, Holden DW, Way M, Caron E. Nck and Cdc42 co-operate to recruit N-WASP to promote FcgammaR-mediated phagocytosis. J Cell Sci. 2012;125(12):2825–2830. doi:10.1242/jcs.106583.
  • Lorenzi R, Brickell PM, Katz DR, Kinnon C, Thrasher AJ. Wiskott-Aldrich syndrome protein is necessary for efficient IgG-mediated phagocytosis. Blood. 2000;95(9):2943–2946. doi:10.1182/blood.V95.9.2943.009k17_2943_2946.
  • Ribes S, Ebert S, Regen T, et al. Toll-like receptor stimulation enhances phagocytosis and intracellular killing of nonencapsulated and encapsulated Streptococcus pneumoniae by murine microglia. Infect Immun. 2010;78(2):865–871. doi:10.1128/IAI.01110-09.
  • Ribes S, Ebert S, Czesnik D, et al. Toll-like receptor prestimulation increases phagocytosis of Escherichia coli DH5α and Escherichia coli K1 strains by murine microglial cells. Infect Immun. 2009;77(1):557–564. doi:10.1128/IAI.00903-08.
  • Pinheiro CdS, Monteiro APT, Dutra FF, et al. Short-term regulation of FcγR-mediated phagocytosis by TLRs in macrophages: participation of 5-lipoxygenase products. Mediators Inflamm. 2017;2017:2086840. doi:10.1155/2017/2086840.
  • Cervantes JL, Benjamin SJ, Chang Y, et al. The phagosome: meeting point of the myddosome, NLRs, and degraded Borrelia burgdorferi. J Immunol. 2016;196:131.2.
  • Gay NJ. Role of self-organising myddosome oligomers in inflammatory signalling by Toll-like receptors. BMC Biol. 2019;17(1):15. doi:10.1186/s12915-019-0637-5.
  • De Nardo D, Balka KR, Cardona Gloria Y, Rao VR, Latz E, Masters SL. Interleukin 1 receptor–associated kinase 4 (IRAK4) plays a dual role in myddosome formation and Toll-like receptor signalling. J Biol Chem. 2018;293(39):15195–15207. doi:10.1074/jbc.RA118.003314.
  • Balka KR, Nardo DD. Understanding early TLR signaling through the Myddosome. J Leukoc Biol. 2019;105(2):339–351. doi:10.1002/JLB.MR0318-096R.
  • Dustin ML. Signaling at neuro/immune synapses. J Clin Invest. 2012;122(4):1149–1155. doi:10.1172/JCI58705.
  • Luft FC. Mindin your own business. J Mol Med. 2012;90(8):861–863. doi:10.1007/s00109-012-0909-9.
  • Liu YS, Wang LF, Cheng XS, et al. The pattern-recognition molecule mindin binds integrin Mac-1 to promote macrophage phagocytosis via Syk activation and NF-kappaB p65 translocation. J Cell Mol Med. 2019;23(5):3402–3416. doi:10.1111/jcmm.14236.
  • Li Y, Cao C, Jia W, et al. Structure of the F-spondin domain of mindin, an integrin ligand and pattern recognition molecule. EMBO J. 2009;28(3):286–297. doi:10.1038/emboj.2008.288.
  • Lishko VK, Moreno B, Podolnikova NP, Ugarova TP. Identification of human cathelicidin peptide LL-37 as a ligand for macrophage integrin alphaMbeta2 (Mac-1, CD11b/CD18) that promotes phagocytosis by opsonizing bacteria. Res Rep Biochem. 2016;2016(6):39–55. doi:10.2147/RRBC.S107070.
  • Zhang X, Bajic G, Andersen GR, Christiansen SH, Vorup-Jensen T. The cationic peptide LL-37 binds Mac-1 (CD11b/CD18) with a low dissociation rate and promotes phagocytosis. Biochim Biophys Acta. 2016;1864(5):471–478. doi:10.1016/j.bbapap.2016.02.013.
  • Stuart LM, Takahashi K, Shi L, Savill J, Ezekowitz RAB. Mannose-binding lectin-deficient mice display defective apoptotic cell clearance but no autoimmune phenotype. J Immunol. 2005;174(6):3220–3226. doi:10.4049/jimmunol.174.6.3220.
  • Shi L, Takahashi K, Dundee J, et al. Mannose-binding lectin-deficient mice are susceptible to infection with Staphylococcus aureus. J Exp Med. 2004;199(10):1379–1390. doi:10.1084/jem.20032207.
  • Tzircotis G, Braga VMM, Caron E. RhoG is required for both FcγR- and CR3-mediated phagocytosis. J Cell Sci. 2011;124(17):2897–2902. doi:10.1242/jcs.084269.
  • Chimini G, Chavrier P. Function of Rho family proteins in actin dynamics during phagocytosis and engulfment. Nat Cell Biol. 2000;2(10):E191–E196. doi:10.1038/35036454.
  • Tosello-Trampont A-C, Nakada-Tsukui K, Ravichandran KS. Engulfment of apoptotic cells is negatively regulated by rho-mediated signaling. J Biol Chem. 2003;278(50):49911–49919. doi:10.1074/jbc.M306079200.
  • Fairn GD, Grinstein S. How nascent phagosomes mature to become phagolysosomes. Trends Immunol. 2012;33(8):397–405. doi:10.1016/j.it.2012.03.003.
  • Niedergang F, Chavrier P. Signaling and membrane dynamics during phagocytosis: many roads lead to the phagos(R)ome. Curr Opin Cell Biol. 2004;16(4):422–428. doi:10.1016/j.ceb.2004.06.006.
  • Pauwels AM, Trost M, Beyaert R, Hoffmann E. Patterns, receptors, and signals: regulation of phagosome maturation. Trends Immunol. 2017;38(6):407–422. doi:10.1016/j.it.2017.03.006.
  • Hoppe AD, Swanson JA. Cdc42, Rac1, and Rac2 display distinct patterns of activation during phagocytosis. Mol Biol Cell. 2004;15(8):3509–3519. doi:10.1091/mbc.e03-11-0847.
  • Swanson JA, Johnson MT, Beningo K, Post P, Mooseker M, Araki N. A contractile activity that closes phagosomes in macrophages. J Cell Sci. 1999;112(Pt 3):307–316.
  • Rougerie P, Miskolci V, Cox D. Generation of membrane structures during phagocytosis and chemotaxis of macrophages: role and regulation of the actin cytoskeleton. Immunol Rev. 2013;256(1):222–239. doi:10.1111/imr.12118.
  • Greenberg S, el Khoury J, di Virgilio F, Kaplan EM, Silverstein SC. Ca(2+)-independent F-actin assembly and disassembly during Fc receptor-mediated phagocytosis in mouse macrophages. J Cell Biol. 1991;113(4):757–767. doi:10.1083/jcb.113.4.757.
  • Diakonova M, Bokoch G, Swanson JA. Dynamics of cytoskeletal proteins during Fcgamma receptor-mediated phagocytosis in macrophages. Mol Biol Cell. 2002;13(2):402–411. doi:10.1091/mbc.01-05-0273.
  • Coppolino MG, Dierckman R, Loijens J, et al. Inhibition of phosphatidylinositol-4-phosphate 5-kinase Ialpha impairs localized actin remodeling and suppresses phagocytosis. J Biol Chem. 2002;277(46):43849–43857. doi:10.1074/jbc.M209046200.
  • Henry RM, Hoppe AD, Joshi N, Swanson JA. The uniformity of phagosome maturation in macrophages. J Cell Biol. 2004;164(2):185–194. doi:10.1083/jcb.200307080.
  • Lancaster CE, Ho CY, Hipolito VEB, Botelho RJ, Terebiznik MR. Phagocytosis: what’s on the menu? (1). Biochem Cell Biol. 2019;97(1):21–29. doi:10.1139/bcb-2018-0008.
  • Holevinsky KO, Nelson DJ. Membrane capacitance changes associated with particle uptake during phagocytosis in macrophages. Biophys J. 1998;75(5):2577–2586. doi:10.1016/S0006-3495(98)77703-3.
  • Booth JW, Trimble WS, Grinstein S. Membrane dynamics in phagocytosis. Semin Immunol. 2001;13(6):357–364. doi:10.1006/smim.2001.0332.
  • Duclos S, Diez R, Garin J, et al. Rab5 regulates the kiss and run fusion between phagosomes and endosomes and the acquisition of phagosome leishmanicidal properties in RAW 264.7 macrophages. J Cell Sci. 2000;113(19):3531–3541.
  • Poteryaev D, Datta S, Ackema K, Zerial M, Spang A. Identification of the switch in early-to-late endosome transition. Cell. 2010;141(3):497–508. doi:10.1016/j.cell.2010.03.011.
  • Gray M, Botelho RJ. Phagocytosis: hungry, hungry cells. Methods Mol Biol (Clifton, N.J.). 2017;1519:1–16.
  • Pei G, Repnik U, Griffiths G, Gutierrez MG. Identification of an immune-regulated phagosomal Rab cascade in macrophages. J Cell Sci. 2014;127(9):2071–2082. doi:10.1242/jcs.144923.
  • Egami Y, Araki N. Rab20 regulates phagosome maturation in RAW264 macrophages during Fc gamma receptor-mediated phagocytosis. PLoS One. 2012;7(4):e35663. doi:10.1371/journal.pone.0035663.
  • Zhang Z, Zhang T, Wang S, et al. Molecular mechanism for Rabex-5 GEF activation by Rabaptin-5. Elife. 2014;3:e02687. doi:10.7554/eLife.02687.
  • Kitano M, Nakaya M, Nakamura T, Nagata S, Matsuda M. Imaging of Rab5 activity identifies essential regulators for phagosome maturation. Nature. 2008;453(7192):241–245. doi:10.1038/nature06857.
  • Mishra A, Eathiraj S, Corvera S, Lambright DG. Structural basis for Rab GTPase recognition and endosome tethering by the C2H2 zinc finger of Early Endosomal Autoantigen 1 (EEA1). Proc Natl Acad Sci USA. 2010;107(24):10866–10871. doi:10.1073/pnas.1000843107.
  • Simonsen A, Lippe R, Christoforidis S, et al. EEA1 links PI(3)K function to Rab5 regulation of endosome fusion. Nature. 1998;394(6692):494–498. doi:10.1038/28879.
  • Murray JT, Panaretou C, Stenmark H, Miaczynska M, Backer JM. Role of Rab5 in the recruitment of hVps34/p150 to the early endosome. Traffic (Copenhagen, Denmark). 2002;3(6):416–427. doi:10.1034/j.1600-0854.2002.30605.x.
  • Simonsen A, Gaullier JM, D’Arrigo A, Stenmark H. The Rab5 effector EEA1 interacts directly with syntaxin-6. J Biol Chem. 1999;274(41):28857–28860. doi:10.1074/jbc.274.41.28857.
  • McBride HM, Rybin V, Murphy C, Giner A, Teasdale R, Zerial M. Oligomeric complexes link Rab5 effectors with NSF and drive membrane fusion via interactions between EEA1 and syntaxin 13. Cell. 1999;98(3):377–386. doi:10.1016/S0092-8674(00)81966-2.
  • Keller S, Berghoff K, Kress H. Phagosomal transport depends strongly on phagosome size. Sci Rep. 2017;7(1):17068. doi:10.1038/s41598-017-17183-7.
  • Kinchen JM, Ravichandran KS. Identification of two evolutionarily conserved genes regulating processing of engulfed apoptotic cells. Nature. 2010;464(7289):778–782. doi:10.1038/nature08853.
  • Haas AK, Fuchs E, Kopajtich R, Barr FA. A GTPase-activating protein controls Rab5 function in endocytic trafficking. Nat Cell Biol. 2005;7(9):887–893. doi:10.1038/ncb1290.
  • Nordmann M, Cabrera M, Perz A, et al. The Mon1-Ccz1 complex is the GEF of the late endosomal Rab7 homolog Ypt7. Curr Biol. 2010;20(18):1654–1659. doi:10.1016/j.cub.2010.08.002.
  • Cabrera M, Nordmann M, Perz A, et al. The Mon1–Ccz1 GEF activates the Rab7 GTPase Ypt7 via a longin-fold–Rab interface and association with PI3P-positive membranes. J Cell Sci. 2014;127(5):1043–1051. doi:10.1242/jcs.140921.
  • Balderhaar HJ, Ungermann C. CORVET and HOPS tethering complexes - coordinators of endosome and lysosome fusion. J Cell Sci. 2013;126(6):1307–1316. doi:10.1242/jcs.107805.
  • Johansson M, Rocha N, Zwart W, et al. Activation of endosomal dynein motors by stepwise assembly of Rab7-RILP-p150Glued, ORP1L, and the receptor betalll spectrin. J Cell Biol. 2007;176(4):459–471. doi:10.1083/jcb.200606077.
  • Harrison RE, Bucci C, Vieira OV, Schroer TA, 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. 2003;23(18):6494–6506. doi:10.1128/MCB.23.18.6494-6506.2003.
  • Wyroba E, Surmacz L, Osinska M, Wiejak J. Phagosome maturation in unicellular eukaryote Paramecium: the presence of RILP, Rab7 and LAMP-2 homologues. Eur J Histochem. 2007;51(3):163–172.
  • Kinchen JM, Doukoumetzidis K, Almendinger J, et al. A pathway for phagosome maturation during engulfment of apoptotic cells. Nat Cell Biol. 2008;10(5):556–566. doi:10.1038/ncb1718.
  • Akbar MA, Tracy C, Kahr WH, Kramer H. The full-of-bacteria gene is required for phagosome maturation during immune defense in Drosophila. J Cell Biol. 2011;192(3):383–390. doi:10.1083/jcb.201008119.
  • Kramer L, Ungermann C. HOPS drives vacuole fusion by binding the vacuolar SNARE complex and the Vam7 PX domain via two distinct sites. Mol Biol Cell. 2011;22(14):2601–2611. doi:10.1091/mbc.e11-02-0104.
  • Lobingier BT, Merz AJ. Sec1/Munc18 protein Vps33 binds to SNARE domains and the quaternary SNARE complex. Mol Biol Cell. 2012;23(23):4611–4622. doi:10.1091/mbc.e12-05-0343.
  • Baker RW, Jeffrey PD, Zick M, Phillips BP, Wickner WT, Hughson FM. A direct role for the Sec1/Munc18-family protein Vps33 as a template for SNARE assembly. Science. 2015;349(6252):1111–1114. doi:10.1126/science.aac7906.
  • Sun-Wada GH, Tabata H, Kawamura N, Aoyama M, Wada Y. Direct recruitment of H+-ATPase from lysosomes for phagosomal acidification. J Cell Sci. 2009;122(14):2504–2513. doi:10.1242/jcs.050443.
  • Sokolovska A, Becker CE, Ip WK, et al. Activation of caspase-1 by the NLRP3 inflammasome regulates the NADPH oxidase NOX2 to control phagosome function. Nat Immunol. 2013;14(6):543–553. doi:10.1038/ni.2595.
  • Nauseef WM. The phagocyte NOX2 NADPH oxidase in microbial killing and cell signaling. Curr Opin Immunol. 2019;60:130–140. doi:10.1016/j.coi.2019.05.006.
  • Nordenfelt P, Tapper H. Phagosome dynamics during phagocytosis by neutrophils. J Leukocyte Biol. 2011;90(2):271–284. doi:10.1189/jlb.0810457.
  • Marshansky V, Futai M. The V-type H+-ATPase in vesicular trafficking: targeting, regulation and function. Curr Opin Cell Biol. 2008;20(4):415–426. doi:10.1016/j.ceb.2008.03.015.
  • Valles P, Lapointe MS, Wysocki J, Batlle D. Kidney vacuolar H+ -ATPase: physiology and regulation. Semin Nephrol. 2006;26(5):361–374. doi:10.1016/j.semnephrol.2006.07.004.
  • Appelqvist H, Waster P, Kagedal K, Ollinger K. The lysosome: from waste bag to potential therapeutic target. J Mol Cell Biol. 2013;5(4):214–226. doi:10.1093/jmcb/mjt022.
  • Li P, Gu M, Xu H. Lysosomal ion channels as decoders of cellular signals. Trends Biochem Sci. 2019;44(2):110–124. doi:10.1016/j.tibs.2018.10.006.
  • Xu H, Ren D. Lysosomal physiology. Annu Rev Physiol. 2015;77(1):57–80. doi:10.1146/annurev-physiol-021014-071649.
  • Underhill DM, Ozinsky A. Phagocytosis of microbes: complexity in action. Annu Rev Immunol. 2002;20(1):825–852. doi:10.1146/annurev.immunol.20.103001.114744.
  • Savina A, Jancic C, Hugues S, et al. NOX2 controls phagosomal pH to regulate antigen processing during crosspresentation by dendritic cells. Cell. 2006;126(1):205–218. doi:10.1016/j.cell.2006.05.035.
  • Pozzi LA, Maciaszek JW, Rock KL. Both dendritic cells and macrophages can stimulate naive CD8 T cells in vivo to proliferate, develop effector function, and differentiate into memory cells. J Immunol. 2005;175(4):2071–2081.
  • Balderhaar HJ, Lachmann J, Yavavli E, Brocker C, Lurick A, Ungermann C. The CORVET complex promotes tethering and fusion of Rab5/Vps21-positive membranes. Proc Natl Acad Sci USA. 2013;110(10):3823–3828. doi:10.1073/pnas.1221785110.
  • Solinger JA, Spang A. Tethering complexes in the endocytic pathway: CORVET and HOPS. FEBS J. 2013;280(12):2743–2757. doi:10.1111/febs.12151.
  • van der Kant R, Jonker CT, Wijdeven RH, et al. Characterization of the mammalian CORVET and HOPS complexes and their modular restructuring for endosome specificity. J Biol Chem. 2015;290(51):30280–30290. doi:10.1074/jbc.M115.688440.
  • Dayam RM, Saric A, Shilliday RE, Botelho RJ. The Phosphoinositide-gated lysosomal Ca(2+) channel, TRPML1, is required for phagosome maturation. Traffic (Copenhagen, Denmark). 2015;16(9):1010–1026. doi:10.1111/tra.12303.
  • Dayam RM, Sun CX, Choy CH, Mancuso G, Glogauer M, Botelho RJ. The lipid kinase PIKfyve coordinates the neutrophil immune response through the activation of the Rac GTPase. J Immun. 2017;199(6):2096–2105. doi:10.4049/jimmunol.1601466.
  • Zhong XZ, Zou Y, Sun X, et al. Inhibition of transient receptor potential channel mucolipin-1 (TRPML1) by lysosomal adenosine involved in severe combined immunodeficiency diseases. J Biol Chem. 2017;292(8):3445–3455. doi:10.1074/jbc.M116.743963.
  • Colletti GA, Miedel MT, Quinn J, Andharia N, Weisz OA, Kiselyov K. Loss of lysosomal ion channel transient receptor potential channel mucolipin-1 (TRPML1) leads to cathepsin B-dependent apoptosis. J Biol Chem. 2012;287(11):8082–8091. doi:10.1074/jbc.M111.285536.
  • Hazeki K, Nigorikawa K, Takaba Y, et al. Essential roles of PIKfyve and PTEN on phagosomal phosphatidylinositol 3-phosphate dynamics. FEBS Lett. 2012;586(22):4010–4015. doi:10.1016/j.febslet.2012.09.043.
  • Krishna S, Palm W, Lee Y, et al. PIKfyve regulates vacuole maturation and nutrient recovery following engulfment. Dev Cell. 2016;38(5):536–547. doi:10.1016/j.devcel.2016.08.001.
  • Isobe Y, Nigorikawa K, Tsurumi G, et al. PIKfyve accelerates phagosome acidification through activation of TRPML1 while arrests aberrant vacuolation independent of the Ca2+ channel. J Biochem. 2019;165(1):75–84. doi:10.1093/jb/mvy084.
  • Laroux FS, Romero X, Wetzler L, Engel P, Terhorst C. Cutting edge: MyD88 controls phagocyte NADPH oxidase function and killing of gram-negative bacteria. J Immunol. 2005;175(9):5596–5600. doi:10.4049/jimmunol.175.9.5596.
  • Vulcano M, Dusi S, Lissandrini D, et al. Toll receptor-mediated regulation of NADPH oxidase in human dendritic cells. J Immunol. 2004;173(9):5749–5756. doi:10.4049/jimmunol.173.9.5749.
  • Sanjuan MA, Dillon CP, Tait SW, et al. Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis. Nature. 2007;450(7173):1253–1257. doi:10.1038/nature06421.
  • Upadhyay S, Philips JA. LC3-associated phagocytosis: host defense and microbial response. Curr Opin Immunol. 2019;60:81–90. doi:10.1016/j.coi.2019.04.012.
  • Cemma M, Grinstein S, Brumell JH. Autophagy proteins are not universally required for phagosome maturation. Autophagy. 2016;12(9):1440–1446. doi:10.1080/15548627.2016.1191724.
  • Bonilla DL, Bhattacharya A, Sha Y, et al. Autophagy regulates phagocytosis by modulating the expression of scavenger receptors. Immunity. 2013;39(3):537–547. doi:10.1016/j.immuni.2013.08.026.
  • Florey O, Overholtzer M. Autophagy proteins in macroendocytic engulfment. Trends Cell Biol. 2012;22(7):374–380. doi:10.1016/j.tcb.2012.04.005.
  • Florey O, Kim SE, Sandoval CP, Haynes CM, Overholtzer M. Autophagy machinery mediates macroendocytic processing and entotic cell death by targeting single membranes. Nat Cell Biol. 2011;13(11):1335–1343. doi:10.1038/ncb2363.
  • Florey O, Gammoh N, Kim SE, Jiang X, Overholtzer M. V-ATPase and osmotic imbalances activate endolysosomal LC3 lipidation. Autophagy. 2015;11(1):88–99. doi:10.4161/15548627.2014.984277.
  • Heckmann BL, Teubner BJW, Tummers B, et al. LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s disease. Cell. 2019;178(3):536–551.e14. doi:10.1016/j.cell.2019.05.056.
  • Botelho RJ, Hackam DJ, Schreiber AD, Grinstein S. Role of COPI in phagosome maturation. J Biol Chem. 2000;275(21):15717–15727. doi:10.1074/jbc.M910068199.
  • Mantegazza AR, Magalhaes JG, Amigorena S, Marks MS. Presentation of phagocytosed antigens by MHC class I and II. Traffic (Copenhagen, Denmark). 2013;14(2):135–152. doi:10.1111/tra.12026.
  • Arakel EC, Schwappach B. Formation of COPI-coated vesicles at a glance. J Cell Sci. 2018;131(5):jcs209890. doi:10.1242/jcs.209890.
  • Mantegazza AR, Zajac AL, Twelvetrees A, Holzbaur EL, Amigorena S, Marks MS. TLR-dependent phagosome tubulation in dendritic cells promotes phagosome cross-talk to optimize MHC-II antigen presentation. Proc Natl Acad Sci USA. 2014;111(43):15508–15513. doi:10.1073/pnas.1412998111.
  • Mantegazza AR, Guttentag SH, El-Benna J, et al. Adaptor protein-3 in dendritic cells facilitates phagosomal toll-like receptor signaling and antigen presentation to CD4(+) T cells. Immunity. 2012;36(5):782–794. doi:10.1016/j.immuni.2012.02.018.
  • Krajcovic M, Krishna S, Akkari L, Joyce JA, Overholtzer M. mTOR regulates phagosome and entotic vacuole fission. Mol Biol Cell. 2013;24(23):3736–3745. doi:10.1091/mbc.e13-07-0408.
  • Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell. 2010;141(2):290–303. doi:10.1016/j.cell.2010.02.024.
  • Sancak Y, Peterson TR, Shaul YD, et al. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science. 2008;320(5882):1496–1501. doi:10.1126/science.1157535.
  • Groenewoud MJ, Zwartkruis FJ. Rheb and Rags come together at the lysosome to activate mTORC1. Biochem Soc Trans. 2013;41(4):951–955. doi:10.1042/BST20130037.
  • Kim J, Kim E. Rag GTPase in amino acid signaling. Amino Acids. 2016;48(4):915–928. doi:10.1007/s00726-016-2171-x.
  • Jewell JL, Russell RC, Guan KL. Amino acid signalling upstream of mTOR. Nat Rev Mol Cell Biol. 2013;14(3):133–139. doi:10.1038/nrm3522.
  • Schweitzer LD, Comb WC, Bar-Peled L, Sabatini DM. Disruption of the Rag-Ragulator complex by c17orf59 inhibits mTORC1. Cell Rep. 2015;12(9):1445–1455. doi:10.1016/j.celrep.2015.07.052.
  • Zoncu R, Bar-Peled L, Efeyan A, Wang S, Sancak Y, Sabatini DM. mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase. Science. 2011;334(6056):678–683. doi:10.1126/science.1207056.
  • Bar-Peled L, Sabatini DM. Regulation of mTORC1 by amino acids. Trends Cell Biol. 2014;24(7):400–406. doi:10.1016/j.tcb.2014.03.003.
  • Velmurugan R, Ramakrishnan S, Kim M, Ober RJ, Ward ES. Phagocytosis of antibody-opsonized tumor cells leads to the formation of a discrete vacuolar compartment in macrophages. Traffic (Copenhagen, Denmark). 2018;19(4):273–284. doi:10.1111/tra.12552.
  • Yu L, McPhee CK, Zheng L, et al. Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature. 2010;465(7300):942–946. doi:10.1038/nature09076.
  • Saric A, Hipolito VEB, Kay JG, Canton J, Antonescu CN, Botelho RJ. mTOR controls lysosome tubulation and antigen presentation in macrophages and dendritic cells. Mol Biol Cell. 2016;27(2):321–333. doi:10.1091/mbc.e15-05-0272.
  • Kobayashi SD, Malachowa N, DeLeo FR. Influence of microbes on neutrophil life and death. Front Cell Infect Microbiol. 2017;7:159–159. doi:10.3389/fcimb.2017.00159.
  • De Zuani M, Paolicelli G, Zelante T, et al. Mast cells respond to candida albicans infections and modulate macrophages phagocytosis of the fungus. Front Immunol. 2018;9:2829–2829. doi:10.3389/fimmu.2018.02829.
  • Xiao Z, Francis EA, Heinrich V. Frustrated phagocytic spreading of human neutrophils on different densities of surface-immobilized IgG. Biophys J. 2018;114(3):651a. doi:10.1016/j.bpj.2017.11.3515.
  • Kovari DT, Wei W, Chang P, et al. Frustrated phagocytic spreading of J774A-1 macrophages ends in myosin II-dependent contraction. Biophys J. 2016;111(12):2698–2710. doi:10.1016/j.bpj.2016.11.009.
  • Padmore T, Stark C, Turkevich LA, Champion JA. Quantitative analysis of the role of fiber length on phagocytosis and inflammatory response by alveolar macrophages. Biochim Biophys Acta Gen Subj. 2017;1861(2):58–67. doi:10.1016/j.bbagen.2016.09.031.
  • Donaldson K, Poland CA, Murphy FA, MacFarlane M, Chernova T, Schinwald A. Pulmonary toxicity of carbon nanotubes and asbestos - similarities and differences. Adv Drug Deliv Rev. 2013;65(15):2078–2086. doi:10.1016/j.addr.2013.07.014.
  • Etchegaray JI, Elguero EJ, Tran JA, Sinatra V, Feany MB, McCall K. Defective phagocytic corpse processing results in neurodegeneration and can be rescued by TORC1 activation. J Neurosci. 2016;36(11):3170–3183. doi:10.1523/JNEUROSCI.1912-15.2016.
  • Poon IK, Lucas CD, Rossi AG, Ravichandran KS. Apoptotic cell clearance: basic biology and therapeutic potential. Nat Rev Immunol. 2014;14(3):166–180. doi:10.1038/nri3607.
  • Bimczok D, Smythies LE, Waites KB, et al. Helicobacter pylori infection inhibits phagocyte clearance of apoptotic gastric epithelial cells. J Immun. 2013;190(12):6626–6634.
  • Grau A, Tabib A, Grau I, Reiner I, Mevorach D. Apoptotic cells induce NF-κB and inflammasome negative signaling. PLoS One. 2015;10(3):e0122440.
  • Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM. 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. 1998;101(4):890–898. doi:10.1172/JCI1112.
  • Voll RE, Herrmann M, Roth EA, Stach C, Kalden JR, Girkontaite I. Immunosuppressive effects of apoptotic cells. Nature. 1997;390(6658):350–351. doi:10.1038/37022.
  • Rosas M, Liddiard K, Kimberg M, et al. The induction of inflammation by dectin-1 in vivo is dependent on myeloid cell programming and the progression of phagocytosis. J Immunol. 2008;181(5):3549–3557. doi:10.4049/jimmunol.181.5.3549.
  • Lichanska AM, Hume DA. Origins and functions of phagocytes in the embryo. Exp Hematol. 2000;28(6):601–611. doi:10.1016/S0301-472X(00)00157-0.
  • Arandjelovic S, Ravichandran KS. Phagocytosis of apoptotic cells in homeostasis. Nat Immunol. 2015;16(9):907–917. doi:10.1038/ni.3253.
  • Blander JM. The many ways tissue phagocytes respond to dying cells. Immunol Rev. 2017;277(1):158–173. doi:10.1111/imr.12537.
  • Mercer F, Ng SH, Brown TM, Boatman G, Johnson PJ. Trogocytosis: a novel mechanism neutrophils use to kill a large, motile extracellular parasite. J Immunol. 2018;200(1 Suppl):52.41.
  • Joly E, Hudrisier D. What is trogocytosis and what is its purpose? Nat Immunol. 2003;4(9):815–815. doi:10.1038/ni0903-815.
  • Li G, Bethune MT, Wong S, et al. T cell antigen discovery via trogocytosis. Nat Methods. 2019;16(2):183–190. doi:10.1038/s41592-018-0305-7.
  • A-Gonzalez N, Quintana JA, Garcia-Silva S, Mazariegos M, et al. Phagocytosis imprints heterogeneity in tissue-resident macrophages. J Exp Med. 2017;214(5):1281–1296. doi:10.1084/jem.20161375.
  • Labrousse AM, Meunier E, Record J, et al. Frustrated phagocytosis on micro-patterned immune complexes to characterize lysosome movements in live macrophages. Front Immun. 2011;2:51–51. doi:10.3389/fimmu.2011.00051.
  • Mularski A, Marie-Anais F, Mazzolini J, Niedergang F. Observing frustrated phagocytosis and phagosome formation and closure using total internal reflection fluorescence microscopy (TIRFM). Methods Mol Biol (Clifton, N.J.). 2018;1784:165–175.

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