Apoptotic Cells, at All Stages of the Death Process, Trigger Characteristic Signaling Events That Are Divergent from and Dominant over Those Triggered by Necrotic Cells

Current models of autoimmunity suggest that delayed clearance of apoptotic cells leads to the presentation of apoptotic antigens in the context of inflammatory signals, with resultant autoimmunity. These models implicitly assume that, in contrast to early apoptotic cells (that retain membrane integrity), late apoptotic cells (with compromised membranes) act like necrotic cells (which also lack intact membranes), possibly because of the release of proinflammatory intracellular contents. We showed previously that early apoptotic and necrotic cells induce distinct mitogen-activated protein kinase modules in macrophages with which they interact. Exposure to apoptotic cells led to nearly complete inhibition of both basal and macrophage colony-stimulating factor-induced ERK1/2 by macrophages. In contrast, necrotic cells induced ERK1/2. We show here that apoptotic cells also strongly induced both c-Jun N-terminal kinase and p38, whereas necrotic cells had no detectable effect on c-Jun N-terminal kinase and p38. We also compared the signaling events induced in macrophages by exposure to early apoptotic cells, late apoptotic cells, and necrotic cells. The signaling events induced by late apoptotic cells were identical to and just as potent as those induced by early apoptotic cells. Thus, apoptotic cells are functionally equivalent throughout the cell death process, irrespective of membrane integrity. Moreover, the effects of both early and late apoptotic cells on signaling were dominant over those of necrotic cells. These data show that apoptotic cells do not become proinflammatory upon the loss of membrane integrity and are inconsistent with the notion that delayed clearance alone can lead to autoimmunity. Current models of autoimmunity suggest that delayed clearance of apoptotic cells leads to the presentation of apoptotic antigens in the context of inflammatory signals, with resultant autoimmunity. These models implicitly assume that, in contrast to early apoptotic cells (that retain membrane integrity), late apoptotic cells (with compromised membranes) act like necrotic cells (which also lack intact membranes), possibly because of the release of proinflammatory intracellular contents. We showed previously that early apoptotic and necrotic cells induce distinct mitogen-activated protein kinase modules in macrophages with which they interact. Exposure to apoptotic cells led to nearly complete inhibition of both basal and macrophage colony-stimulating factor-induced ERK1/2 by macrophages. In contrast, necrotic cells induced ERK1/2. We show here that apoptotic cells also strongly induced both c-Jun N-terminal kinase and p38, whereas necrotic cells had no detectable effect on c-Jun N-terminal kinase and p38. We also compared the signaling events induced in macrophages by exposure to early apoptotic cells, late apoptotic cells, and necrotic cells. The signaling events induced by late apoptotic cells were identical to and just as potent as those induced by early apoptotic cells. Thus, apoptotic cells are functionally equivalent throughout the cell death process, irrespective of membrane integrity. Moreover, the effects of both early and late apoptotic cells on signaling were dominant over those of necrotic cells. These data show that apoptotic cells do not become proinflammatory upon the loss of membrane integrity and are inconsistent with the notion that delayed clearance alone can lead to autoimmunity. Apoptosis is an active energy-dependent process that generally occurs without inflammation or injury to surrounding tissues (1Majno G. Joris I. Am. J. Pathol. 1995; 14: 3-15Google Scholar). Apoptotic cells express surface markers that permit their rapid recognition and ingestion by phagocytes (2Platt N. da Silva R.P. Gordon S. Trends Cell Biol. 1998; 8: 365-372Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar, 3Savill J. Fadok V. Nature. 2000; 407: 784-788Crossref PubMed Scopus (1281) Google Scholar). Moreover, the cell membrane of cells undergoing apoptosis remains intact until relatively late (1Majno G. Joris I. Am. J. Pathol. 1995; 14: 3-15Google Scholar). Thus, the vast majority of cells dying by apoptosis are cleared by phagocytes while their cell membranes are still intact and before they can release their potentially inflammatory intracellular contents. In this view, the noninflammatory behavior of apoptotic cells is essentially passive in that inflammation is avoided by rapid and efficient clearance of apoptotic cells. In fact, apoptotic cells are also actively anti-inflammatory (4Fadok V.A. Bratton D.L. Konowal A. Freed P.W. Westcott J.Y. Henson P.M. J. Clin. Investig. 1998; 101: 890-898Crossref PubMed Scopus (2577) Google Scholar, 5Cocco R.E. Ucker D.S. Mol. Biol. Cell. 2001; 12: 919-930Crossref PubMed Scopus (166) Google Scholar). For example, the uptake of apoptotic cells actively inhibits the release of proinflammatory mediators such as interleukin 1 and tumor necrosis factor-α by macrophages (mφ) 2The abbreviations used are: mφ, macrophage(s); BM, bone marrow; ERK1/2, extracellular signal-regulated kinase 1 and 2; MAPK, mitogen-activated protein kinase; M-CSF, macrophage colony-stimulating factor; JNK, c-Jun N-terminal kinase; FBS, fetal bovine serum; LCM, L929 cell conditioned medium; PI, propidium iodide. (4Fadok V.A. Bratton D.L. Konowal A. Freed P.W. Westcott J.Y. Henson P.M. J. Clin. Investig. 1998; 101: 890-898Crossref PubMed Scopus (2577) Google Scholar, 5Cocco R.E. Ucker D.S. Mol. Biol. Cell. 2001; 12: 919-930Crossref PubMed Scopus (166) Google Scholar, 6Voll R.E. Hermann M. Roth E.A. Stach C. Kalden J.R. Nature. 1997; 390: 350-351Crossref PubMed Scopus (1513) Google Scholar). This contrasts with the effect of necrotic cell uptake, which may lead to mφ activation and the release of proinflammatory cytokines (7Fadok V.A. Bratton D.L. Guthrie L. Henson P.M. J. Immunol. 2001; 166: 6847-6854Crossref PubMed Scopus (312) Google Scholar). Based on this differential response to apoptotic versus necrotic cells, antigens derived from cells dying by these two distinct processes are thought to have opposite effects on the activation of T cells (8Skoberne M. Beignon A.S. Larsson M. Bhardwaj N. Curr. Top. Microbiol. Immunol. 2005; 289: 259-292PubMed Google Scholar). The proinflammatory effects of necrotic cells may act as a “danger signal” and provide the costimulation required for T cell activation and immunity. In contrast, early apoptotic cells, being anti-inflammatory, are unlikely to activate T cells and may even be tolerogenic (9Gaipl U.S. Voll R.E. Sheriff A. Franz S. Kalden J.R. Herrmann M. Autoimmun. Rev. 2005; 4: 189-194Crossref PubMed Scopus (181) Google Scholar). The effect of late apoptotic cells (apoptotic cells that have lost membrane integrity), also referred to as post-apoptotic or secondarily necrotic cells, is more uncertain (10Cvetanovic M. Ucker D.S. J. Immunol. 2004; 172: 880-889Crossref PubMed Scopus (159) Google Scholar). According to many current models, late apoptotic cells should behave like necrotic cells, because of the release of potentially inflammatory intracellular contents (11Wu X. Molinaro C. Johnson N. Casiano C.A. Arthritis Rheum. 2001; 44: 2642-2652Crossref PubMed Scopus (103) Google Scholar). Indeed, there is a prevailing belief that delayed or reduced clearance of apoptotic cells leads to the presentation of apoptotic antigen in the context of inflammatory signals, with resultant autoimmunity (9Gaipl U.S. Voll R.E. Sheriff A. Franz S. Kalden J.R. Herrmann M. Autoimmun. Rev. 2005; 4: 189-194Crossref PubMed Scopus (181) Google Scholar, 12Herrmann M. Voll R.E. Zoller O.M. Hagenhofer M. Ponner B.B. Kalden J.R. Arthritis Rheum. 1998; 41: 1241-1250Crossref PubMed Scopus (716) Google Scholar, 13Baumann I. Kolowos W. Voll R.E. Manger B. Gaipl U. Neuhuber W.L. Kirchner T. Kalden J.R. Herrmann M. Arthritis Rheum. 2002; 46: 191-201Crossref PubMed Scopus (465) Google Scholar). This view is supported by studies in mice in which genetic deficiencies of any number of gene products (for example, C1q (14Mitchell D.A. Pickering M.C. Warren J. Fossati-Jimack L. Cortes-Hernandez J. Cook H.T. Botto M. Walport M.J. J. Immunol. 2002; 168: 2538-2543Crossref PubMed Scopus (206) Google Scholar), the MER receptor tyrosine kinase (15Cohen P.L. Caricchio R. Abraham V. Camenisch T.D. Jennette J.C. Roubey R.A. Earp H.S. Matsushima G. Reap E.A. J. Exp. Med. 2002; 196: 135-140Crossref PubMed Scopus (517) Google Scholar), or MFG-E8 (16Hanayama R. Tanaka M. Miyasaka K. Aozasa K. Koike M. Uchiyama Y. Nagata S. Science. 2004; 304: 1147-1150Crossref PubMed Scopus (809) Google Scholar)) give rise both to delayed clearance of apoptotic cells and to the development of systemic autoimmune disease. This apparent linkage may not reflect a causal relationship between altered clearance and autoimmunity. As we and others have shown, the recognition and/or uptake of apoptotic cells is accompanied by intracellular signal transduction (17Reddy S.M. Hsiao K.H. Abernethy V.E. Fan H. Longacre A. Lieberthal W. Rauch J. Koh J.S. Levine J.S. J. Immunol. 2002; 169: 702-713Crossref PubMed Scopus (92) Google Scholar, 18Giles K.M. Ross K. Rossi A.G. Hotchin N.A. Haslett C. Dransfield I. J. Immunol. 2001; 167: 976-986Crossref PubMed Scopus (140) Google Scholar). For example, although necrotic cells activate the mitogen-activated protein kinase (MAPK) elements extracellular signal-regulated kinase (ERK) 1 and 2, apoptotic cells strongly inhibit ERK1/2 activity (17Reddy S.M. Hsiao K.H. Abernethy V.E. Fan H. Longacre A. Lieberthal W. Rauch J. Koh J.S. Levine J.S. J. Immunol. 2002; 169: 702-713Crossref PubMed Scopus (92) Google Scholar). We hypothesize that it is the absence of appropriate apoptotic cell-induced signaling events, rather than delayed apoptotic cell clearance per se, that is responsible for the loss of tolerance and the development of autoimmunity in these mutant mice. A strong prediction of our hypothesis is that signaling events triggered by late apoptotic cells should resemble those of early apoptotic cells and not necrotic cells. In accord with previous work, we show here that early apoptotic and necrotic cells induce distinct MAPK modules. Consistent with our and in to the delayed clearance of we that the signaling events induced in mφ by late apoptotic cells are identical to those induced by early apoptotic cells. our data that both early and late apoptotic cells are dominant over necrotic cells with to MAPK these data that delayed clearance of apoptotic cells, in and of is unlikely to autoimmunity and suggest that the signaling events induced by apoptotic cells, early or may a in the of of the were from or were the active of to with to or irrespective of of of the the active or of and and and and were ERK1/2 the from the of the active the derived from the of the active of the the derived from the of the active of the Cell of bone mφ were as previously J.S. A. J. Immunol. PubMed Scopus Google Scholar). cells were from the and of or mice. cells were by the cell in of and for The cells were in and in in FBS, with and L929 cell conditioned as a of of an mφ were the and with to the cells for in signaling the with without for The T cell and the cell Levine J.S. S. Lieberthal W. Am. J. 2005; PubMed Scopus Google were used as a of apoptotic and necrotic cells. cells were in FBS, 1 and cells were in FBS, and of and Apoptotic and of cells induced by cells to bovine and 1 Apoptosis by exposure to for by and in bovine apoptotic cells were used for an and late apoptotic cells were used for an Apoptosis of cells that to and the cells were by the of exposure to of both and cells induced by cells in and cells in the appropriate to for from were used in studies as a in of apoptotic or necrotic cells. of apoptosis and necrosis by cells were as cells that were both propidium and apoptotic cells were as cells with and cell cells were as cells of or cell apoptotic cells were as cells with and cell The loss of membrane integrity in necrosis and late apoptosis also by these early apoptotic cell early apoptotic and late apoptotic cells. cell necrotic cells. apoptotic cell late apoptotic cells. In cells, as cells of without of the cell cells were in 1 1 1 1 and The were for and the were for protein by the protein were by to membranes and with to the Apoptotic and on the ERK1/2 apoptotic and necrotic cells to have differential effects on the signaling events induced by exposure to these two of cells be In accord with this we have previously that apoptotic and necrotic cells have opposite effects on ERK1/2 signaling (17Reddy S.M. Hsiao K.H. Abernethy V.E. Fan H. Longacre A. Lieberthal W. Rauch J. Koh J.S. Levine J.S. J. Immunol. 2002; 169: 702-713Crossref PubMed Scopus (92) Google Scholar). should be that the necrotic cells used in our although membrane are intact cells and have a as by and (17Reddy S.M. Hsiao K.H. Abernethy V.E. Fan H. Longacre A. Lieberthal W. Rauch J. Koh J.S. Levine J.S. J. Immunol. 2002; 169: 702-713Crossref PubMed Scopus (92) Google Scholar). exposure to necrotic cells ERK1/2 in of mφ, as by the on and exposure to apoptotic cells both basal and ERK1/2 activity (17Reddy S.M. Hsiao K.H. Abernethy V.E. Fan H. Longacre A. Lieberthal W. Rauch J. Koh J.S. Levine J.S. J. Immunol. 2002; 169: 702-713Crossref PubMed Scopus (92) Google Scholar). this differential behavior in we the of the ERK1/2 response to apoptotic and necrotic cells of mφ were to and by for in mφ showed of basal active ERK1/2. with for induced nearly of ERK1/2. In the absence of M-CSF, exposure to early apoptotic cells induced no ERK1/2 in fact, in basal ERK1/2 In contrast, exposure to necrotic cells for ERK1/2 in a a necrotic cell to mφ of a of to and the response a of a had no effect on ERK1/2 Apoptotic and necrotic cells alone no ERK1/2 in these S.M. Hsiao K.H. Abernethy V.E. Fan H. Longacre A. Lieberthal W. Rauch J. Koh J.S. Levine J.S. J. Immunol. 2002; 169: 702-713Crossref PubMed Scopus (92) Google and data not We the effect that exposure to these for had on activation of ERK1/2 by exposure to early apoptotic cells strongly of ERK1/2. by early apoptotic cells in a an apoptotic cell to mφ of a of and complete a of In contrast, exposure to necrotic cells the of ERK1/2 of with Thus, the to early apoptotic and necrotic cells were not opposite in also in apoptotic cells were more potent a effect an of as compared with a of for necrotic cells. had no effect on ERK1/2 in response to these effects on ERK1/2 we the of of the kinase an of ERK1/2. We the ERK1/2 on the activation of M. S. Mol. Cell PubMed Scopus Google Scholar). As in 2, the of for in response to early apoptotic cells, necrotic cells, and that for of ERK1/2. apoptotic cells strongly in response to M-CSF, whereas necrotic cells alone induced of that the protein of equivalent on and to that of ERK1/2 and exposure to apoptotic cells be to of intact macrophage by derived from apoptotic cells, we and we for ERK1/2, p38, and As in and the of ERK1/2 and were equivalent and not by exposure to apoptotic cells. This of of ERK1/2 and exposure to apoptotic cells, that from apoptotic cells a of macrophage cell exposure to necrotic cells had no effect on the of ERK1/2 and should also be that effects are not a in the of necrotic cells, because they ERK1/2 and Moreover, as exposure to apoptotic cells not ERK1/2 and also induced the activation of and the were for it is unlikely that a can such signaling We identical with early apoptotic and necrotic cells derived from cells not with our previous (17Reddy S.M. Hsiao K.H. Abernethy V.E. Fan H. Longacre A. Lieberthal W. Rauch J. Koh J.S. Levine J.S. J. Immunol. 2002; 169: 702-713Crossref PubMed Scopus (92) Google Scholar), we that these effects on ERK1/2 are of early apoptotic and necrotic cells, of the or of the cells. We have effects on ERK1/2 activation with of the T cells, cells, and and The of apoptotic cells to inhibit ERK1/2 activation is also of the with which death is induced and S.M. Hsiao K.H. Abernethy V.E. Fan H. Longacre A. Lieberthal W. Rauch J. Koh J.S. Levine J.S. J. Immunol. 2002; 169: 702-713Crossref PubMed Scopus (92) Google and data not Moreover, these effects of early apoptotic and necrotic cells on ERK1/2 are not to mφ also to because early apoptotic cells factor-induced ERK1/2 in data not J. V. B. S. Y. T. L. S. J. S. and S. for We that early apoptotic and necrotic cells, without to or have and effects on the and activation of ERK1/2. Apoptotic and on MAPK the effects of early apoptotic and necrotic cells on two MAPK and and mφ had of and p38. induced of and had no effect on In contrast to their effect on ERK1/2 early apoptotic cells induced of both and p38. The of the and to early apoptotic cells were to that of the ERK1/2 the and modules are in response to a of and inflammatory J. Rev. 2001; PubMed Scopus Google Scholar), exposure to necrotic cells had no detectable effect on these two alone and or to not like necrotic cells, had no effect on the of and not These data our of the of the effects of early apoptotic and necrotic cells on the MAPK modules. The of Apoptotic over of that early apoptotic and necrotic cells have effects on the ERK1/2, and modules a with which to the effect of of these two on mφ signaling in the delayed clearance of autoimmunity is the that the proinflammatory effects of necrotic cells, like those for late apoptotic cells, should over those of early apoptotic cells. We this in two of In the and we mφ with a number of necrotic cells of in with a number of apoptotic cells, the of apoptotic to necrotic cells from to In the and we a number of apoptotic cells inhibition of ERK1/2 in with a number of necrotic cells, the of apoptotic to necrotic cells from to in both of and with to MAPK the effects of apoptotic cells were strongly dominant over those of necrotic cells. For example, apoptotic cells were an number for ERK1/2 no number of necrotic cells to even the apoptotic cell signal and an number of necrotic cells for of ERK1/2 1 apoptotic necrotic cells to the necrotic cell effect and This is in that a number of apoptotic cells (with to ERK1/2 still to inhibit the response to an number of necrotic cells. the of Apoptotic to Apoptotic of these we late apoptotic cells, which have lost membrane still retain the behavior of early apoptotic cells. apoptotic cells were by a exposure to These cells the of late reduced cell and to or apoptotic cells were not and were to mφ in their that mφ were not to the late apoptotic cells also to any intracellular contents that may have late apoptotic cells induced the MAPK response as early apoptotic cells and Thus, late apoptotic cells ERK1/2 and and also of and p38. the of late apoptotic cells to that of early apoptotic cells. We also the relationship of late apoptotic cells and necrotic cells the two were with mφ and We that late apoptotic cells were as as early apoptotic cells in of ERK1/2 and in response to necrotic cells. apoptotic cells also induced of and p38, irrespective of the or of necrotic cells. We that, with to of ERK1/2, and p38, late apoptotic cells behave to early apoptotic cells. Thus, of membrane apoptotic cells have a effect on mφ signal in to MAPK signaling events, and this effect is strongly dominant over that of necrotic cells. Apoptotic of apoptotic cells with to ERK1/2, and signaling may the release of proinflammatory intracellular contents from late apoptotic cells. As in we this by a of late apoptotic cells the (apoptotic and intracellular cells and cell intracellular and (apoptotic intracellular 2, and were derived from late apoptotic cell to an apoptotic to mφ cell of inhibition of ERK1/2 for the that the may and were derived from late apoptotic cell to a apoptotic to mφ cell of to mφ as a of the from late apoptotic cells, the the intracellular contents from late apoptotic cells, induced ERK1/2 and mφ were with exposure to these for inhibition of ERK1/2 with of the the for which we an We that the activity of apoptotic cells in the membrane derived from those cells, apoptotic and cell We no proinflammatory activity in any of the the intracellular contents from late apoptotic cells. derived from a of necrotic cells induced ERK1/2 and In contrast to apoptotic cells, the proinflammatory activity with necrotic cells is both and that apoptotic cells and necrotic cells signaling in These previous that recognition of apoptotic cells and necrotic cells by mφ occurs distinct R.E. Ucker D.S. Mol. Biol. Cell. 2001; 12: 919-930Crossref PubMed Scopus (166) Google and that recognition processes are to signaling cells activate ERK1/2, whereas apoptotic cells inhibit ERK1/2, of the We data that with apoptotic cells ERK1/2 apoptotic cells also can inhibit previously ERK1/2 not (17Reddy S.M. Hsiao K.H. Abernethy V.E. Fan H. Longacre A. Lieberthal W. Rauch J. Koh J.S. Levine J.S. J. Immunol. 2002; 169: 702-713Crossref PubMed Scopus (92) Google Scholar). Apoptotic cells also activate and p38, whereas necrotic cells have no detectable effect on these two MAPK modules. We that the effects of apoptotic cells on signaling like their effects on R.E. Ucker D.S. Mol. Biol. Cell. 2001; 12: 919-930Crossref PubMed Scopus (166) Google Scholar), are dominant over those of necrotic cells and can be even the apoptotic cells are in reduced is to that both and derived from necrotic cells can the effects by necrotic cells. our data that apoptotic cells retain the to their signaling throughout the death process, irrespective of membrane integrity. Indeed, the effects of late apoptotic cells are identical in to those of early apoptotic cells. intracellular contents from late apoptotic cells are and not may have for our of autoimmunity and tolerance studies suggest that necrotic and apoptotic cells have effects on Rev. Immunol. 2004; 4: PubMed Scopus Google Scholar). cells, by of their inflammatory intracellular may provide the costimulation for activation of T cells and may A. Clin. Exp. Immunol. 2002; PubMed Scopus Google Scholar). Apoptotic cells, on the being actively anti-inflammatory, do not activate T cells, and may even be tolerogenic S. W. L. C. M. A. N. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). According to current models, late apoptotic cells, which have lost membrane integrity and their intracellular should behave like necrotic cells and induce an response J. Dransfield I. C. Haslett C. Rev. Immunol. 2002; PubMed Scopus Google Scholar). Thus, delayed or clearance of cells, as with of the protein C1q (14Mitchell D.A. Pickering M.C. Warren J. Fossati-Jimack L. Cortes-Hernandez J. Cook H.T. Botto M. Walport M.J. J. Immunol. 2002; 168: 2538-2543Crossref PubMed Scopus (206) Google or the MER receptor tyrosine kinase (15Cohen P.L. Caricchio R. Abraham V. Camenisch T.D. Jennette J.C. Roubey R.A. Earp H.S. Matsushima G. Reap E.A. J. Exp. Med. 2002; 196: 135-140Crossref PubMed Scopus (517) Google Scholar), is thought to lead to presentation of apoptotic antigen in the context of inflammatory signals, with resultant autoimmunity The delayed clearance that we for necrotic and apoptotic cells to have effects on the signaling events induced by exposure to these two of cells be This prediction is in of signaling events the JNK, and MAPK modules. the that late apoptotic cells, which have lost membrane should behave like necrotic cells. in contrast to this late apoptotic cells were from early apoptotic cells in of their effects on apoptotic cells basal and ERK1/2 late apoptotic cells and p38, as in the prediction of the delayed clearance late apoptotic cells were dominant over necrotic cells. the that the signaling events induced by necrotic cells be dominant over those induced by apoptotic cells. This prediction from the apoptotic cells are in delayed clearance of apoptotic cells lead to the of both early and late apoptotic cells. the inflammatory in response to the inflammatory intracellular contents of late apoptotic cells can the anti-inflammatory effects of early apoptotic cells. the intracellular contents of necrotic cells should be as inflammatory as those of late cells, we apoptotic cells necrotic cells. in contrast to the prediction of the delayed clearance the signaling events induced by apoptotic cells were dominant over those induced by necrotic cells. late apoptotic cells were just as dominant as early apoptotic cells in of ERK1/2 activity and and p38. Thus, in contrast to the of the delayed clearance apoptotic cells to be functionally equivalent throughout their irrespective of membrane integrity. in to the delayed clearance from late apoptotic cells our the delayed clearance of there is an studies on MAPK signaling and may not to signal transduction is that there signaling and/or for which the of the delayed clearance and that these a more in the between tolerance and immunity. This because we have also that late apoptotic cells early apoptotic cells with to proinflammatory activity (10Cvetanovic M. Ucker D.S. J. Immunol. 2004; 172: 880-889Crossref PubMed Scopus (159) Google and inflammatory R.E. Ucker D.S. Mol. Biol. Cell. 2001; 12: 919-930Crossref PubMed Scopus (166) Google Scholar). Moreover, even delayed clearance to the development of it is not in and of to because of or the leads to the in of apoptotic cells in the absence of autoimmunity A. C.A. C. A. S.M. J. Cell Biol. 2004; 167: PubMed Scopus Google Scholar, K. L. J. R.A. J. Immunol. 2005; PubMed Scopus Google Scholar). In of these we that the absence of apoptotic cell-induced signaling events, rather than delayed apoptotic cell clearance per se, is the to the loss of tolerance and the development of autoimmunity. We hypothesize that the signaling induced by the and/or uptake of apoptotic cells are to the of tolerance and that or signaling events these can to autoimmunity. Consistent with this we have previously that mφ from mice of the models of that systemic as as the autoimmune have an identical apoptotic in the of cytokines J.S. Levine J.S. J. Immunol. 2000; PubMed Scopus Google Scholar, A. Koh J.S. Hsiao H. Fan H. V.A. Levine J.S. J. Biol. 2004; PubMed Scopus Google Scholar, H. Longacre A. V. Hsiao Koh J.S. Levine J.S. J. Immunol. 2004; 172: PubMed Scopus Google Scholar, H. V.A. Longacre A. Levine J.S. J. Biol. PubMed Scopus Google Scholar). systemic and in can be in that in the absence of apoptotic cells, by these is is not the apoptotic in mφ from mice. mφ from and the systemic also have a in the activity of the protein a of the in of and H. Longacre A. V. Hsiao Koh J.S. Levine J.S. J. Immunol. 2004; 172: PubMed Scopus Google Scholar, H. V.A. Longacre A. Levine J.S. J. Biol. PubMed Scopus Google Scholar). no were in mφ from These provide strong for our hypothesis that in the signaling events induced by apoptotic cells may be to the development of autoimmunity. The of these signaling events, in of gene and are the of with

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