Draper-mediated and Phosphatidylserine-independent Phagocytosis of Apoptotic Cells by Drosophila Hemocytes/Macrophages

The mechanism of phagocytic elimination of dying cells in Drosophila is poorly understood. This study was undertaken to examine the recognition and engulfment of apoptotic cells by Drosophila hemocytes/macrophages in vitro and in vivo. In the in vitro analysis, l(2)mbn cells (a cell line established from larval hemocytes of a tumorous Drosophila mutant) were used as phagocytes. When l(2)mbn cells were treated with the molting hormone 20-hydroxyecdysone, the cells acquired the ability to phagocytose apoptotic S2 cells, another Drosophila cell line. S2 cells undergoing cycloheximide-induced apoptosis exposed phosphatidylserine on their surface, but their engulfment by l(2)mbn cells did not seem to be mediated by phosphatidylserine. The level of Croquemort, a candidate phagocytosis receptor of Drosophila hemocytes/macrophages, increased in l(2)mbn cells after treatment with 20-hydroxyecdysone, whereas that of Draper, another candidate phagocytosis receptor, remained unchanged. However, apoptotic cell phagocytosis was reduced when the expression of Draper, but not of Croquemort, was inhibited by RNA interference in hormone-treated l(2)mbn cells. We next examined whether Draper is responsible for the phagocytosis of apoptotic cells in vivo using an assay for engulfment based on assessing DNA degradation of apoptotic cells in dICAD mutant embryos (which only occurred after ingestion by the phagocytes). RNA interference-mediated decrease in the level of Draper in embryos of mutant flies was accompanied by a decrease in the number of cells containing fragmented DNA. Furthermore, histochemical analyses of dispersed embryonic cells revealed that the level of phagocytosis of apoptotic cells by hemocytes/macrophages was reduced when Draper expression was inhibited. These results indicate that Drosophila hemocytes/macrophages execute Draper-mediated phagocytosis to eliminate apoptotic cells. The mechanism of phagocytic elimination of dying cells in Drosophila is poorly understood. This study was undertaken to examine the recognition and engulfment of apoptotic cells by Drosophila hemocytes/macrophages in vitro and in vivo. In the in vitro analysis, l(2)mbn cells (a cell line established from larval hemocytes of a tumorous Drosophila mutant) were used as phagocytes. When l(2)mbn cells were treated with the molting hormone 20-hydroxyecdysone, the cells acquired the ability to phagocytose apoptotic S2 cells, another Drosophila cell line. S2 cells undergoing cycloheximide-induced apoptosis exposed phosphatidylserine on their surface, but their engulfment by l(2)mbn cells did not seem to be mediated by phosphatidylserine. The level of Croquemort, a candidate phagocytosis receptor of Drosophila hemocytes/macrophages, increased in l(2)mbn cells after treatment with 20-hydroxyecdysone, whereas that of Draper, another candidate phagocytosis receptor, remained unchanged. However, apoptotic cell phagocytosis was reduced when the expression of Draper, but not of Croquemort, was inhibited by RNA interference in hormone-treated l(2)mbn cells. We next examined whether Draper is responsible for the phagocytosis of apoptotic cells in vivo using an assay for engulfment based on assessing DNA degradation of apoptotic cells in dICAD mutant embryos (which only occurred after ingestion by the phagocytes). RNA interference-mediated decrease in the level of Draper in embryos of mutant flies was accompanied by a decrease in the number of cells containing fragmented DNA. Furthermore, histochemical analyses of dispersed embryonic cells revealed that the level of phagocytosis of apoptotic cells by hemocytes/macrophages was reduced when Draper expression was inhibited. These results indicate that Drosophila hemocytes/macrophages execute Draper-mediated phagocytosis to eliminate apoptotic cells. Cells undergoing apoptosis are selectively and rapidly eliminated from the organism by phagocytosis (1Wyllie A.H. Kerr J.F.R. Currie A.R. Int. Rev. Cytol. 1980; 68: 251-306Crossref PubMed Scopus (6728) Google Scholar, 2Ellis R.E. Yuan J. Horvitz H.R. Annu. Rev. Cell Biol. 1991; 7: 663-698Crossref PubMed Scopus (1946) Google Scholar). This process contributes not only to the clearance of unnecessary or spent cells from the body but also to maintaining tissue homeostasis (3Ren Y. Savill J. Cell Death Differ. 1998; 5: 563-568Crossref PubMed Scopus (309) Google Scholar, 4Savill J. Fadok V. Nature. 2000; 407: 784-788Crossref PubMed Scopus (1281) Google Scholar, 5Steinman R.M. Turley S. Mellman I. Inaba K. J. Exp. Med. 2000; 191: 411-416Crossref PubMed Scopus (1015) Google Scholar, 6Walport M.J. Nat. Genet. 2000; 25: 135-136Crossref PubMed Scopus (126) Google Scholar, 7Fadok V.A. Bratton D.L. Henson P.M. J. Clin. Invest. 2001; 108: 957-962Crossref PubMed Scopus (405) Google Scholar, 8Rosen A. Casciola-Rosen L. Nat. Med. 2001; 7: 664-665Crossref PubMed Scopus (83) Google Scholar). The mechanism underlying phagocytosis of apoptotic cells consists of various distinct events such as the migration of phagocytes toward the site of apoptosis, the recognition and engulfment of apoptotic cells by phagocytes, processing of engulfed apoptotic cells in phagocytes, and alteration of gene expression in engulfing phagocytes. Although investigation of these phenomena has recently become intensive, the molecular basis of each event largely remains unclear. The phagocytic elimination of apoptotic cells is considered to be an innate immune response, because the underlying mechanism does not require the action of protein products of rearranged genes (9Greenberg S. Grinstein S. Curr. Opin. Immunol. 2002; 14: 136-145Crossref PubMed Scopus (439) Google Scholar, 10Gordon S. Cell. 2002; 111: 927-930Abstract Full Text Full Text PDF PubMed Scopus (948) Google Scholar, 11Roos A. Xu W. Castellano G. Nauta A.J. Garred P. Daha M.R. van Kooten C. Eur. J. Immunol. 2004; 34: 921-929Crossref PubMed Scopus (148) Google Scholar). Thus, clarification of the mechanisms and consequences of this phenomenon should lead to a better understanding of the cellular response in innate immunity. Apoptotic cells bind to phagocytes through recognition of marker molecules that are expressed at their surfaces (4Savill J. Fadok V. Nature. 2000; 407: 784-788Crossref PubMed Scopus (1281) Google Scholar, 12Savill J. Brit. Med. Bull. 1997; 53: 491-508Crossref PubMed Scopus (284) Google Scholar), the best characterized of which is the membrane phospholipid phosphatidylserine (PS) 1The abbreviations used are: PS, phosphatidylserine; BSA, bovine serum albumin; CAD, caspase-activated DNase; FBS, fetal bovine serum; FITC, fluorescein isothiocyanate; ICAD, the inhibitor of CAD; ISNT, in situ nick translation; PBS, phosphate-buffered saline; PFA, paraformaldehyde; PC, phosphatidylcholine. (13Fadok V.A. Bratton D.L. Frasch S.C. Warner M.L. Henson P.M. Cell Death Differ. 1998; 5: 551-562Crossref PubMed Scopus (624) Google Scholar, 14Chimini G. Cell Death Differ. 2001; 8: 545-548Crossref PubMed Scopus (16) Google Scholar, 15Schlegel R.A. Williamson P. Cell Death Differ. 2001; 8: 551-563Crossref PubMed Scopus Google Scholar, K. A.J. Annu. Rev. PubMed Scopus Google Scholar). is to the of the membrane but to the and is exposed on the cell apoptosis (13Fadok V.A. Bratton D.L. Frasch S.C. Warner M.L. Henson P.M. 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Cell Death Differ. 2001; 8: 545-548Crossref PubMed Scopus (16) Google Scholar, Cell Death Differ. 2001; 8: PubMed Scopus Google Scholar, Horvitz H.R. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). responsible for the (which and which is by the C. of the gene for the receptor Fadok V.A. K. Henson P. S. PubMed Scopus Google Scholar). of the genes that phagocytes the to apoptotic cells K. S. Cell. 2004; 14: Full Text Full Text PDF PubMed Scopus Google Scholar). the is the dying cells and phagocytes in Croquemort, a of the of J. Full Text Full Text PDF PubMed Scopus Google Scholar), is expressed in hemocytes/macrophages J. Full Text Full Text PDF PubMed Scopus Google and has to be in the clearance of apoptotic cells in Drosophila embryos P. K. PubMed Scopus Google Scholar). to be to or and for the of remains the Draper, which is by is a Drosophila of and is expressed in of phagocytes, and hemocytes/macrophages M.R. J. J. Full Text Full Text PDF PubMed Scopus Google Scholar). Draper is another candidate phagocytosis receptor in this In of the in embryos an increased number of apoptotic in the the of this in phagocytosis of apoptotic M.R. J. J. Full Text Full Text PDF PubMed Scopus Google Scholar). is that at of the in C. also in Although the of the Drosophila of the gene for the receptor has V.A. Bratton D.L. A. Henson P.M. Nature. 2000; PubMed Scopus Google Scholar), in phagocytosis in Drosophila is number of cells apoptosis of Drosophila and are eliminated through phagocytosis by hemocytes or K. PubMed Google Scholar, M.J. J. PubMed Scopus Google Scholar). In the examined the of phagocytosis of apoptotic cells in Drosophila in vitro and in on the of on cells and and Draper on phagocytes. Cell and cells by S. established from larval hemocytes of a tumorous Drosophila mutant PubMed Scopus Google were at in Drosophila containing fetal bovine serum and l(2)mbn cells at were with for S2 cells by S. were at in containing FBS, and and to apoptosis by with for were from after to as A. S. S. Y. 1998; PubMed Scopus Google Scholar). cells, a were in containing at with in and to apoptosis by with for The of apoptosis was by the by by cells with the DNA by in situ nick and by the of A. Y. Y. J. Biol. 1997; Full Text Full Text PDF PubMed Scopus (126) Google or the C. Cell Death Differ. PubMed Scopus Google by the of apoptosis, S2 cells were with the inhibitor at the in the for and treatment with and flies by S. the of which is a mutant with expression of the inhibitor of caspase-activated or caspase-activated Y. S. 2002; PubMed Scopus Google Scholar), were with and a of at were on containing and to at of apoptosis, embryos that for at after were exposed to and for at as K. PubMed Google Scholar). was by with a at the of Croquemort, which was expressed in as a protein with with and which was an of Draper M.R. J. J. Full Text Full Text PDF PubMed Scopus Google Scholar), and to which was a to a for I. L. Nat. Cell Biol. 2002; PubMed Scopus Google Scholar), were by and was from the of and were using only or a of and at a of as A. Y. Y. J. Biol. 1997; Full Text Full Text PDF PubMed Scopus (126) Google Scholar). were by in at of examine the of l(2)mbn cells with were with for at and with phosphate-buffered containing bovine serum and the of was examined by or protein for l(2)mbn cells were in of and and at for with The were at for and the were in this were in and by and a The membrane was with with and was with and the were using the the of embryonic embryos were treated with for in and at for and in the were as of in S2 cells, cells on were with containing and and by treatment with The cells were with containing BSA, with PBS, and with were with fluorescein with and examined by in l(2)mbn cells, cells were treated with PBS, and serum in and with in The cells were with with in PBS, and with and The cells were with in PBS, with and examined a Draper in l(2)mbn cells, cells were treated with a of and in and in The cells were with with in PBS, and with The were with and examined by of in Drosophila embryos were with a of and for for and with and to were with PBS, by treatment with containing and for and for with containing and for The were with containing BSA, and at The embryos were with PBS, treated with with and examined by In S2 cells for the of containing fragmented the cells were on with PFA, with and with containing were to in situ DNA in the of DNA and and for at The were with containing with and examined a the of dispersed embryonic cells, embryos were with and through a using a and the was The were with PBS, treated with and and with to the action of and through a The dispersed cells were by with PBS, and used for embryonic cells were by as for S2 cells, that the were with and from and were the of embryos were with a of and for for and with and to were treated with with and in containing The embryos were to in situ DNA and examined as for S2 cells. In cells on in were with and containing for at with and and with S2 cells or cells which with in and The was at for the in the with PBS, and treated with containing PFA, and and The were examined by and the number of l(2)mbn cells that cells was and expressed to the number of l(2)mbn cells the phagocytic examine the phagocytosis of or l(2)mbn cells treated or not treated with were with the or for the in the with PBS, as and examined by The of phagocytosis was as for the assay with cells as were with or S2 cells which to apoptosis by treatment with as in containing for at in the or of In using cells, the were and with and the of phagocytosis was by In using S2 cells as the of phagocytosis was as for the using l(2)mbn cells as phagocytes. In of apoptotic cells in embryos was examined by embryos of dICAD mutant flies of at by as of the of Draper in embryos of dICAD mutant flies were to RNA interference using RNA containing the Draper as and to for at The embryos with embryos with were as and with a of and for for were on and were using The were with and to as that a treatment with was to DNA in a were and a by embryos in a of each were in this and and of the number of were in embryos was also examined by histochemical of dispersed embryonic cells from this embryonic cells were by and using and the of phagocytes that engulfed apoptotic cells was cells were dispersed as with containing and BSA, and with containing BSA, and for The cells were with (a marker of or (a marker of in the used for The were with containing and and with of or of The cells were to in situ DNA with and examined as cells in were examined for the in and The number of or cells that was and expressed to or cells as the phagocytic RNA to the and the site of or the and of was by using the J. Full Text Full Text PDF PubMed Scopus Google by or Draper from the Drosophila as a The were used as for of RNA from using a RNA The RNA was by and to and the were used in after the of was by l(2)mbn cells that as were with and in the containing the RNA and for The were with of containing FBS, and and at for These cells were for phagocytic as as the level of and Draper by as the expression of Draper in Drosophila embryos were after on and with of RNA The embryos were to for at and for the level of Draper as as for the of phagocytosis as of Cell cells treated or not treated with 20-hydroxyecdysone, were with for at and with The cells were with and for on The were at for at and were The cells were with for at with The were with with and for at The were to and the were for the of Draper by as from analyses are expressed as the analyses were by and of were considered of Apoptotic Cells by l(2)mbn Drosophila cell line established from tumorous larval hemocytes PubMed Scopus Google Scholar), that the ability to phagocytose another or when with the molting hormone Biol. 1997; PubMed Scopus Google Scholar). We examined l(2)mbn cells treated with for of the ability to phagocytose apoptotic cells. S2 cells, another Drosophila cell were as the cells. various for apoptosis in S2 cells, that treatment with the protein inhibitor S2 cells of of DNA of of and of The of cells with fragmented and were and The of by treatment was inhibited in the of a inhibitor These results indicate that S2 cells S2 cells treated with were with and with l(2)mbn cells that in the of When the was examined by after membrane and the of S2 cells were l(2)mbn cells or by S2 cells in l(2)mbn cells were considered to and the of l(2)mbn cells that engulfed S2 cells was and expressed as the phagocytic of the l(2)mbn cells with was to the to phagocytose S2 cells The phagocytosis by hormone-treated l(2)mbn cells also on treatment of S2 cells with cells were not and the of a inhibitor treatment inhibited S2 cells from to The of phagocytosis by l(2)mbn cells to for at with the level of phagocytosis of by l(2)mbn cells not as Biol. 1997; PubMed Scopus Google but did not the phagocytosis of These results indicate that treatment with the ability of l(2)mbn cells to phagocytose apoptotic cells phagocytic of Apoptotic S2 Cells by l(2)mbn next examined whether or not phagocytosis of S2 cells by l(2)mbn cells is mediated by The of on phagocytosis was and the results that the level of phagocytosis was not by the of containing or not containing from of apoptotic but not S2 cells, and the phagocytosis was inhibited by the of the hormone-treated l(2)mbn cells apoptotic cells, another at only a level their ingestion by not of by hormone-treated l(2)mbn cells was The results that and of were by l(2)mbn cells These results indicate that phagocytosis of S2 cells by l(2)mbn cells is not mediated by PS, because l(2)mbn cells treated with not of Draper but of in by l(2)mbn next candidate phagocytosis in l(2)mbn cells. membrane as phagocytosis in Drosophila Croquemort, a of the of and Draper, a Drosophila of C. of which are expressed in with l(2)mbn cells to become and of the expression of in l(2)mbn cells by revealed that the of cells the receptor increased from to after The of in l(2)mbn cells was to that in cells J. Full Text Full Text PDF PubMed Scopus Google Scholar). The results of an a of of Draper to that of Croquemort, and was in the or of in l(2)mbn cells treated and not treated with The expression of was by a of of l(2)mbn cells, in which a distinct at was We the level of Draper by of l(2)mbn cells a at with an expressed Draper and of the with the Draper protein the from the is that the of Draper by M.R. J. J. Full Text Full Text PDF PubMed Scopus Google is the in l(2)mbn cells. of Drosophila embryos at a in that the of Draper is expressed in l(2)mbn cells and at at the The level of Draper expression in l(2)mbn cells, by with from or remained the after hormone Draper protein from hormone-treated cells to in a that from cells. These results indicate that treatment with an in the level of but not of Draper in l(2)mbn cells. This the that in the phagocytosis of apoptotic cells by l(2)mbn cells. examine the for or Draper, phagocytosis were using l(2)mbn cells in which the level of expression of each protein was reduced by RNA l(2)mbn cells that treated with were in the of RNA that a of the of each When of cells were examined by that with the RNA the level of the receptor but on the expression of the These l(2)mbn cells with cells that were not to RNA interference were used in phagocytosis with apoptotic S2 cells as In to of expression did not and a decrease in the level of Draper a of the level of phagocytosis This was not to of the phagocytic of l(2)mbn cells but to be for phagocytosis of apoptotic cells, because phagocytosis of or by l(2)mbn cells was not and These results indicate that Draper, but not Croquemort, is at in for phagocytosis of apoptotic S2 cells by l(2)mbn cells. of Draper in of Apoptotic Cells by in Drosophila whether Draper is in the phagocytosis of apoptotic cells by hemocytes/macrophages in was to a to the of apoptotic cells in this used embryos of a Drosophila mutant in which a gene for dICAD is Y. S. 2002; PubMed Scopus Google Scholar). dICAD mutant flies not because of the of dICAD K. A. S. J. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). a is apoptotic DNA in the mutant flies Y. S. 2002; PubMed Scopus Google Scholar). We that DNA in embryos of the mutant at should be the of degradation of apoptotic cell DNA after engulfment by phagocytes. this embryonic cells were examined for the of containing fragmented DNA. embryos of at of or dICAD mutant flies were by of embryos and the number of in the mutant embryos was that in embryos examine whether in embryos were from of engulfed cells, cells in embryos were to ISNT, and of were another cell and the from cells We considered the to be from apoptotic cells that and the to be from cells in embryos of whereas in dispersed cells of the mutant embryos were cells We that apoptosis does in embryos of the dICAD mutant this embryos at of at when hemocytes/macrophages or not A. V. PubMed Google Scholar), were exposed to for of apoptosis and examined for the of apoptotic cells. to in the of cells containing in or dICAD mutant but only in embryos These results indicate that embryonic cells of the dICAD mutant did apoptosis, was not accompanied by DNA after to of the that apoptotic cells in the mutant embryos become only after engulfment by phagocytes, and the of phagocytosis of apoptotic cells in Drosophila embryos be examined in situ using dICAD mutant flies based on the of cells with fragmented DNA. We examined the of Draper in phagocytosis of apoptotic cells in embryos of dICAD mutant flies by the level of Draper expression by RNA at an of remained cells, were with RNA and by after were to to when hemocytes/macrophages that these cells at We whether the expression of Draper of the RNA that was used to Draper expression in l(2)mbn cells. The level of Draper was with on the level of that the RNA inhibited the expression of Draper in the results were using embryos of the dICAD mutant flies not When the mutant embryos were by for the level of phagocytosis of apoptotic cells, the number of in embryos with the RNA was of that with embryos that of or were These results indicate that Draper is responsible at for the phagocytic elimination of apoptotic cells in Drosophila The of Draper in the phagocytosis of apoptotic by has M.R. J. J. Full Text Full Text PDF PubMed Scopus Google Scholar), and embryos at the examined in to We the cell of phagocytes, hemocytes/macrophages, or engulfment of apoptotic cells in embryos is mediated by cells in embryos of flies that with RNA or were dispersed and examined by and We used that the marker or the marker in the We that cells marker protein that hemocytes/macrophages and are in the phagocytosis of apoptotic cells in Drosophila embryos were for hemocytes/macrophages and using embryos with a level of phagocytosis by each of phagocytic of and were with hemocytes/macrophages and not These remained the when embryos were with We that the level of phagocytosis by of was reduced by when Draper expression was inhibited by RNA interference The number of hemocytes/macrophages or in dispersed embryonic cells did not after of the Draper RNA not These results to that Draper is at in for phagocytic elimination of apoptotic cells by hemocytes/macrophages and in Drosophila The of Draper in the phagocytosis of apoptotic cells by M.R. J. J. Full Text Full Text PDF PubMed Scopus Google was in a of phagocytosis of Draper, the Drosophila of C. in of Apoptotic has that are that lead to the of engulfment in phagocytes. These are to be by distinct to be mediated by distinct and to and The membrane and to in the in C. In Croquemort, a of the of is the only protein to be in phagocytosis of apoptotic cells by However, to be to or and the of or for phagocytosis remains Drosophila of C. was recently to a in phagocytosis by of Draper expression an in the number of apoptotic in the of Drosophila M.R. J. J. Full Text Full Text PDF PubMed Scopus Google Scholar). In the the of Draper in in a that Draper is also in the phagocytosis of apoptotic cells by Drosophila This that at of the for phagocytosis of apoptotic cells in C. in the the of a Drosophila of the receptor has V.A. Bratton D.L. A. Henson P.M. Nature. 2000; PubMed Scopus Google Scholar), but in the phagocytosis of apoptotic cells in Drosophila remains to be that Draper was not responsible for the phagocytosis by larval cell line embryonic hemocytes/macrophages, or embryonic the of phagocytosis in phagocytes. at for l(2)mbn cells, that a of the receptor is a phagocytosis receptor, because phagocytosis by l(2)mbn cells was not to be mediated by on the of apoptotic cells. this is not whether or not as a phagocytosis marker at in for is that Draper engulfment of apoptotic cells in phagocytes by a a on the of The for remains to be not to be by this receptor, because in this study that phagocytosis of apoptotic S2 cells by l(2)mbn cells is mediated by Draper with on membrane protein protein also as with and is considered to be K. Y. G. Henson P.M. J. Biol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). Henson and A. Bratton Fadok V.A. Henson P.M. J. Exp. Med. 2001; PubMed Scopus Google that as a phagocytosis receptor to with a molecular in the In the of in the phagocytosis of by hemocytes of another was recently S. J. PubMed Scopus Google Scholar). mutant and another molecular in the a reduced level of phagocytosis of of these to not at the recognition but at events phagocytosis by A. G. J. 2001; PubMed Scopus Google Scholar). Furthermore, has to to the of cells Y. K. J. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). and which in are for the of of of l(2)mbn Cells by with did not the phagocytic of l(2)mbn cells but the level of phagocytosis of apoptotic cells or This that the hormone in l(2)mbn cells that are not for phagocytosis of apoptotic cells. be an in the of Draper at the of the but that this was not the In the of in l(2)mbn cells increased treatment with the but the results of an RNA interference that this receptor was not in the phagocytosis of apoptotic cells by l(2)mbn cells. is that Draper is in hormone-treated l(2)mbn cells. This be because that migration of Draper protein in a a after treatment with Although of of or Draper has results that Draper is through for or and by We are this by Drosophila innate immune consists of and cellular Annu. Rev. Immunol. 2002; PubMed Scopus Google Scholar). In the of which are through the action of the body (a of the of and at or Nat. Immunol. 2002; PubMed Scopus Google Scholar). the the cellular in Drosophila of phagocytosis and of by of which events lead to of the Nat. Immunol. 2002; PubMed Scopus Google Scholar). Although the mechanism of the has characterized Nat. Immunol. 2002; PubMed Scopus Google Scholar, Nature. PubMed Scopus Google Scholar), Drosophila hemocytes remains to be of apoptotic cells by hemocytes is considered of the cellular immune response of that Draper is in phagocytosis of apoptotic cells but not of We that distinct are by Drosophila hemocytes for the recognition of apoptotic cells and these recognition is for a better understanding of cellular innate in We S. S. the the Drosophila and the of for We are also to for

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