Masking of Phosphatidylserine Inhibits Apoptotic Cell Engulfment and Induces Autoantibody Production in Mice

Asano, Kenichi; Miwa, Miyu; Miwa, Keiko; Hanayama, Rikinari; Nagase, Hiroko; Nagata, Shinji; Tanaka, Masato

doi:10.1084/jem.20040342

Cited by 245 publications

(216 citation statements)

References 40 publications

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“…MFG-E8 is a bridging molecule that stimulates phagocytosis of apoptotic cells through specific binding to PS on apoptotic cells via COOH-terminal factor VIII homologous domain and to avb3 integrin expressed on phagocytes via an NH 2 -terminal EGF-like domain. 88 They have shown that coexpression of MFG-E8 inhibits vaccination activity of irradiated GM-CSF-secreting tumor cells in the B16 melanoma model, whereas an MFG-E8 mutant potentiates GM-CSF-induced tumor destruction. 87 Interestingly, this MFG-E8 mutant retains the capacity to bind PS on apoptotic cells but contains a modified integrin-binding domain that inhibits phagocytosis of apoptotic cells.…”

Section: Exploitation Of Molecules On the Surface Of Dying Cells For mentioning

confidence: 99%

“…87 Interestingly, this MFG-E8 mutant retains the capacity to bind PS on apoptotic cells but contains a modified integrin-binding domain that inhibits phagocytosis of apoptotic cells. 87,88 A possible explanation for this anti-tumor effect may be that the MFG-E8 mutant inhibits the clearance of irradiated apoptotic tumor cells by masking PS on apoptotic cells, which then become secondary necrotic cells thereby enhancing immunogenecity. These findings suggest that shielding of PS on apoptotic cells by mutant MFG-E8 or annexin-V together with the adjuvant activity of GM-CSF may provide a novel combined anti-tumor strategy.…”

Section: Exploitation Of Molecules On the Surface Of Dying Cells For mentioning

confidence: 99%

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From regulation of dying cell engulfment to development of anti-cancer therapy

Krysko

Vandenabeele

2007

Cell Death Differ

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Cell death and efficient engulfment of dying cells ensure tissue homeostasis and is involved in pathogenesis. Clearance of dying cells is a complex and dynamic process coordinated by interplay between ligands on dying cell, bridging molecules, and receptors on engulfing cells. In this review, we will discuss recent advances and significance of molecular changes on the surface of dying cells implicated in their recognition and clearance as well as factors released by dying cells that attract macrophages to the site of cell death. It is now becoming apparent that phagocytes use a specific set of mechanisms to discriminate between live and dead cells, and this phenomenon will be illustrated here. Next, we will discuss potential mechanisms by which removal of dying cells could modulate immune responses of phagocytes, in particular of macrophages. Finally, we will address possible strategies for manipulating the immunogenicity of dying cells in experimental cancer therapies.

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Section: Exploitation Of Molecules On the Surface Of Dying Cells For mentioning

confidence: 99%

Section: Exploitation Of Molecules On the Surface Of Dying Cells For mentioning

confidence: 99%

From regulation of dying cell engulfment to development of anti-cancer therapy

Krysko

Vandenabeele

2007

Cell Death Differ

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“…Injection of mutant MFG-E8 (engineered to mask PS and reduce apoptotic cell uptake) also elicits autoimmune responses, particularly when administered along with apoptotic cells. 29 Since apoptotic cells are considered the original antigenic insult, the consequences of the early autoimmune response to surface components on such cells assume obvious importance. It is probable that both the nature of the antigens recognized as well as the nature of the elicited antibodies and their downstream biological effects could influence the future course of disease.…”

Section: Reactivity Of the Immunizing Antibody (Rn86) Is Shown For Rementioning

confidence: 99%

Anti-idiotype-mediated epitope spreading and diminished phagocytosis by a human monoclonal antibody recognizing late-stage apoptotic cells

et al. 2006

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Apoptotic cells are considered an important auto-antigenic source in diseases such as systemic lupus erythematosus (SLE). A human monoclonal antibody demonstrating exquisite specificity towards late-stage apoptotic cells was generated from an SLE patient. Polyreactive recognition of ribonucleoproteins Ro52 and Ro60 was observed. The antibody significantly diminished the phagocytosis of apoptotic cells and a concomitant decrease in transforming growth factor-b (TGF-b) secretion was observed. Light and heavy chain sequencing revealed the antibody to be in essentially germline configuration. Elicited anti-idiotypic antibodies bound distinct self-antigens and showed augmented reactivity towards apoptotic cells as well. Thus, near-germline encoded antibodies recognizing antigens externalized during the process of apoptosis can mediate a variety of potentially pathogenic effects; decreases in the phagocytic uptake of dying cells would constitute a disease-perpetuating event and stimulation of the idiotypic network could lead to intermolecular epitope spreading, increasing the range of molecular targets.

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“…24 Others have speculated that PS molecules on viable cells could somehow be masked, and unavailable for recognition by macrophages. 11 However, masking of externalized PS in vivo by administration of a mutant form of MFG-E8 was recently found to trigger autoantibody production in mice, 25 making this an unlikely explanation. On the other hand, it is conceivable that viable cells could express other, dominant signals that discourage engulfment in spite of PS externalization.…”

Section: Emerging Roles For Ps Signaling In Nonapoptotic Cellsmentioning

confidence: 99%

PS externalization: from corpse clearance to drug delivery

Fadeel¹,

Xue²

2005

Cell Death Differ

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Phosphatidylserine (PS) externalization on the plasma membrane of aging red blood cells and on apoptotic cell corpses serves as a common recognition signal for macrophages. 1 Perturbation of phospholipid asymmetry and rapid redistribution of PS also occurs in platelets and provides a procoagulant surface that promotes blood clotting. 2 In addition, several recent studies have revealed novel roles for altered plasma membrane phospholipid distribution in nonapoptotic cells. The aim of the present discourse is to highlight these emerging roles for PS externalization, and some of the putative therapeutic implications thereof. PS signaling is required for programmed cell clearancePhospholipid asymmetry is a common feature of all eukaryotic membranes. Moreover, mitotic and quiescent cells invest considerable amounts of energy to generate and maintain membrane lipid sidedness. Loss of phospholipid asymmetry and the concomitant externalization of PS can be readily monitored by the use of fluorescence-conjugated annexin V, an endogenous protein that specifically binds to PS, and this process has been well studied in platelets. Thus, when platelets are activated by agonists, such as thrombin and collagen, PS is rapidly brought to the surface of the cell. Exposed PS then catalyzes the assembly of proteins of the coagulation system, leading to a conversion of soluble fibrinogen into an insoluble fibrin clot. 2 The pivotal role of PS externalization is illustrated in Scott syndrome, a bleeding disorder characterized by an impaired Ca 2 þ -induced phospholipid scrambling, and hence an inability of platelets to promote blood coagulation. 2 Apoptotic cells are also procoagulant, and annexin V can completely abolish the procoagulant activity, suggesting that this effect is PS-dependent. 3 More recent findings suggest that annexin V-induced internalization of tissue factor (TF), the initiator of blood coagulation, may also contribute to the anticoagulant functions of annexin V (discussed below).The ability of PS to act as a signal for in vivo recognition and clearance of effete cells was demonstrated 20 years ago in studies of red blood cells. 4 Subsequent studies by Fadok et al. 5 showed that PS externalization also can trigger specific recognition and removal of apoptotic cells, and the exposition of PS was soon found to be a common, if not universal, event during apoptosis. 6 More recent studies have shown that PS externalization is, in fact, essential for corpse clearance by macrophages and nonprofessional phagocytes (fibroblasts). 1 Moreover, our studies have indicated that the generation of oxidized PS species (PS-OX) is an integral part of the apoptosis program. 7 Externalization of PS-OX on the cell surface potentiates macrophage engulfment of apoptotic cells, and could also serve to promote the binding of so-called bridging molecules (serum proteins) to apoptotic cell corpses. 8 Interestingly, deletion in mice of the PS-binding bridging molecule, milk fat globule epidermal growth factor 8 (MFG-E8) (also known as lactadhe...

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Masking of Phosphatidylserine Inhibits Apoptotic Cell Engulfment and Induces Autoantibody Production in Mice

Cited by 245 publications

References 40 publications

From regulation of dying cell engulfment to development of anti-cancer therapy

From regulation of dying cell engulfment to development of anti-cancer therapy

Anti-idiotype-mediated epitope spreading and diminished phagocytosis by a human monoclonal antibody recognizing late-stage apoptotic cells

PS externalization: from corpse clearance to drug delivery

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