Articles |
From the Department of Medicine, University of California San Diego, La Jolla, Calif.
| Abstract |
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receptors by the anti-Fc
RII/RIII antibody 2.4G2 triggers the
phagocytosis of bound VaRBCs. Phagocytosis is also triggered by
subthreshold opsonization of VaRBC, ie, by antibody concentrations that
do not by themselves cause binding and phagocytosis of native RBCs.
Finally, treatment with low concentrations of
glutaraldehyde, which causes membrane protein
cross-linking, promotes the phagocytosis of VaRBCs, but, at the low
concentration used, has little or no effect on binding and phagocytosis
of native RBCs. We suggest that the internalization of damaged cells,
bound because of PS exposure, requires the cooperation of a PS-binding
receptor with at least one additional receptor to trigger an
intracellular signaling pathway to initiate phagocytosis.
Key Words: macrophages apoptosis scavenger receptors
| Introduction |
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We have previously demonstrated that recognition of OxRBCs by mouse peritoneal macrophages is mediated by a receptor with affinity for both membrane PS and OxLDL.14 We also showed that recognition of OxRBCs is inhibited by polyanionic molecules such as fucoidan, polyinosinic acid, and malondialdehyde-modified albumin,16 all characteristic inhibitors of binding to scavenger receptors (reviewed in Reference 1717 ). However, AcLDL did not interfere with OxRBC binding. This observation raised the possibility that alternative receptors recognizing OxLDL might be involved. Recently, macrosialin and the scavenger receptor class B members (SRBI and CD36) have been shown also to bind PS-containing liposomes.18 19 However, a functional role for these proteins in mediating recognition of cell membranes expressing surface PS has not yet been demonstrated.
While there is considerable evidence that an increase in PS content of the external leaflet of cell membranes, particularly membranes of aging or oxidatively damaged RBCs, is a basis for their recognition by macrophages, the properties and nature of the receptor(s) involved remain unknown. Identification of the specific ligand domains recognized by scavenger receptors is difficult because of the structural complexity of the damaged membrane on which the ligand resides. Sodium vanadate has proven useful in generating a ligand with less complexity as a result of its ability to specifically inhibit the RBC aminophospholipid translocase and thereby create cells expressing PS on their membrane surface but avoiding additional changes resulting from oxidation.20 We previously demonstrated that treatment of RBCs with vanadate produced RBCs that were comparable to OxRBCs in the levels of exposed surface PS and their propensity to be bound by macrophages.14 Vanadate treatment thus seemed to provide a simplified model for studying PS receptor activity in macrophages. Interestingly, VaRBCs, unlike OxRBCs, were not readily phagocytosed by macrophages despite avid binding.
The present studies were undertaken to further characterize the interactions between macrophages, OxRBCs, and VaRBCs, taking advantage of the dissociation between binding and phagocytosis, which we have previously reported.14
| Methods |
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RII/RIII mAb (2.4G2)21
from Pharmingen. Mouse monoclonal IgG1 anti-human
glycophorin A (10F7) was a generous gift of Dr A. Rearden (University
of California, San Diego)22 ; rat mAb 2F8, directed against
the mouse AcLDL receptor was a generous gift from Dr I. Fraser, D.A.
Hughes, and Dr S. Gordon (University of Oxford,
UK).23
Lipoproteins
Human LDL (d=1.019 to 1.063) was isolated in EDTA (1
mg/mL) from fresh plasma by preparative
ultracentrifugation as previously
described.24 Acetylation of LDL with
acetic anhydride was as described by Basu et
al.25
Cells
Human RBCs were isolated as previously
described.16 OxRBCs (4% hematocrit in PBS were prepared
by incubating at 37°C for 90 minutes in the presence of 0.2
mmol/L CuSO4 plus 5 mmol/L ascorbate as
previously described.16 Membrane phospholipid
asymmetry was disrupted by treatment with 100 µmol/L sodium
orthovanadate (10% hematocrit in PBS) for 18 to 20 hours. In some
experiments, RBCs were treated with glutaraldehyde or
with an antibody against glycophorin A by incubating for 45 minutes at
37° on a shaker (concentrations shown with data below).
Resident mouse peritoneal macrophages were isolated by peritoneal lavage as previously described16 and plated in RPMI 1640 supplemented with 10% fetal bovine serum and gentamycin. After 4 hours, nonadherent cells were removed by washing three times with PBS. Macrophages were used immediately after the washing step because overnight incubation results in an acquired ability to bind even normal human RBCs via a sialic aciddependent mechanism. The adherent macrophages were kept in Dulbecco's modified Eagle's medium for binding and phagocytosis experiments.
Binding and Phagocytosis Assays
RBCs (hematocrit 0.1%) were incubated with
macrophages at 37°C for 1 hour. After washing to remove
unbound RBCs, the percentage of macrophages binding (and/or
phagocytosing) one or more RBCs was determined as previously
described.16 Macrophage-bound RBCs were
removed by hypotonic lysis with 5 mmol/L phosphate buffer and
macrophages were fixed with methanol before determination of
RBC phagocytosis.
| Results |
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The failure of VaRBCs to undergo phagocytosis even when they expressed
an amount of PS on the external leaflet comparable to that found in
OxRBCs implied that oxidation must alter the RBC in an additional way
or ways that account for the triggering of their phagocytosis. It has
been previously shown that the complement receptor CR3 (iC3b receptor)
on neutrophils and monocytes will bind iC3b-coated particles but will
not phagocytose them unless the cells are first activated with
PMA. On the other hand, when ß-glucan particles bind CR3, they are
phagocytosed without any need to add PMA, presumably because ß-glucan
can itself promote phagocytosis, either through a distinct receptor or
specific binding to a distinct region of
CR3.24 27 Because of the parallelism between
these findings and our findings with VaRBCs versus OxRBCs, we tested
whether the addition of PMA would trigger phagocytosis of VaRBCs. As
shown in Fig 3
pretreatment of
macrophages with PMA for 10 minutes led to a significant
induction of VaRBC phagocytosis, increasing to a level comparable to
that seen with OxRBCs,14 16 but with no apparent
change in the overall binding. This effect was prevented by
preincubating the macrophages for 15 minutes with 1
µmol/L staurosporine, suggesting a role for protein
kinase C in the induction of phagocytosis. To rule out a nonspecific
cytotoxic effect of staurosporine, we did a duplicate study
using normal RBCs opsonized with a mAb against human glycophorin A.
Phagocytosis was not inhibited.
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The nature of the additional changes induced by oxidation that
promote OxRBC phagocytosis is not known. Possibilities include
structural changes, such as membrane protein cross-linking or
proteolytic degradation, generating new ligands recognized by a
signaling receptor.28 Phagocytosis of
apoptotic cells by CD36 requires that it interact with the
vitronectin receptor
(
vß3), and RGDS
peptide has been shown to inhibit interaction of that complex with
thrombospondin and to inhibit also the phagocytosis of
apoptotic cells.29 We tested for any
potential involvement of this system in the phagocytosis of VaRBCs but,
as shown in Fig 4
, RGDS neither inhibited
nor significantly enhanced phagocytosis.
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Cross-linking of Fc receptors due to binding of immune complexes or of
antibodies against the Fc receptor causes protein tyrosine
phosphorylation30 and can trigger
phagocytosis. We therefore tried adding an antibody to the
Fc
RII/RIII receptor during the binding of VaRBCs to
macrophages. As shown in Fig 4
, this significantly increased
phagocytosis of VaRBCs.
Although AcLDL does not compete for binding of VaRBCs to macrophages, it is the most characteristic ligand for some scavenger receptors17 and could in principle interact with one or more of them to trigger phagocytosis. However, addition of neither AcLDL nor 2F8 (a mAb against scavenger receptor A) had any effect (data not shown).
To extend our investigation and draw a closer analogy to what might be
happening with OxRBCs, we tested several modifications of VaRBCs to see
if they could trigger their phagocytosis. A critical requirement was
that the modification would not by itself mediate significant binding
to the macrophage. It is known that senescent RBCs isolated
from healthy volunteers contain associated autoantibodies, but in
numbers too few to promote binding or
phagocytosis.31 However, if these senescent RBCs
are additionally opsonized with complement component C3b, efficient
phagocytosis is observed.31 32 33 By analogy, we
asked whether binding of a small number of IgG antibodies to a VaRBC
might be sufficient to stimulate subsequent phagocytosis without
contributing significantly to adherence. Both native and VaRBCs were
opsonized with an IgG1 antibody directed against
glycophorin A (10F7) using several dilutions of antibody-containing
hybridoma medium to find concentrations that did not result in
significant binding or phagocytosis of native RBCs. As shown in Fig 5
, mild opsonization at the
concentrations shown had little or no effect on binding but increased
VaRBC phagocytosis significantly. There was no comparable increase in
phagocytosis of native RBCs.
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It has been shown previously that treatment of RBCs with aldehydes can
increase their binding and phagocytosis by macrophages much as
treatment with oxygen radicals does.16 34 We
previously showed that glutaraldehyde-treated RBCs were
recognized by a macrophage scavenger receptor similar or
identical to that which recognizes OxRBCs.16
Currently it is not clear whether recognition of these RBCs is mediated
by aldehyde-modified membrane components per se or by exposed membrane
PS. In any case, it is clear that aldehyde treatment produces RBCs that
are readily phagocytosed. Conditions were found under which
glutaraldehyde treatment of native RBCs resulted in
only minimal binding and phagocytosis by macrophages yet
generated membrane protein cross-linking detectable by
SDSpolyacrylamide gel electrophoresis (data not shown). We
tested whether similar glutaraldehyde treatment of
VaRBCs would increase their phagocytosis. As shown in Fig 6
, binding and phagocytosis of native
RBCs was not significantly affected by the
glutaraldehyde concentrations used, whereas
phagocytosis of VaRBCs was increased at least threefold. These results
demonstrate that changes produced by glutaraldehyde
that are by themselves unable to mediate significant macrophage
adherence can stimulate phagocytosis of bound VaRBCs.
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| Discussion |
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The phagocytosis of cells targeted for removal by macrophages is a two-step process initiated by recognition and binding of the target followed by its internalization. The dissociation between binding and internalization of damaged cells described here exemplifies the independence of ligand binding from ligand internalization: Binding is not necessarily followed by internalization; rather, internalization may be dependent on the activation state of the macrophage or the cooperation of additional membrane components. In our model, the PS receptor appears to function primarily as an adhesion receptor for damaged cells because VaRBCs are bound but are not internalized. In the case of OxRBCs, recognition is achieved in the same way, but internalization of the damaged cell is initiated by a signaling event probably resulting from an interaction with a distinct macrophage receptor(s). The membrane topography of OxRBCs is quite complex due to the various structural changes induced by oxidation, and many of these newly formed "epitopes" could potentially stimulate phagocytosis without necessarily contributing to adherence to the macrophage. By analogy, apoptotic cells also recognized by virtue of their membrane PS, may exhibit additional unknown ligands that promote their phagocytosis.
Initiation of phagocytosis requires cytoskeletal rearrangement at the point of particle contact, a process that is triggered by intracellular signals. Phagocytosis-promoting receptors such as the Fc receptor are able to stimulate actin polymerization and internalization through multiple signaling pathways.41 The signaling event induced by ligation of Fc or fibronectin receptors has been shown to assist phagocytosis via CR3, which is itself able to bind C3bi-coated particles but is inefficient in mediating their internalization.26 42 Binding of VaRBCs to the macrophage receptor does not itself stimulate phagocytosis, suggesting that, like CR3, the putative PS receptor may require the cooperation of additional membrane receptors if internalization is to occur. We have shown here that opsonization of VaRBCs with antibody concentrations that are insufficient to mediate binding of normal RBCs can promote the phagocytosis of bound VaRBCs by mouse peritoneal macrophages. Similarly, membrane changes induced by glutaraldehyde treatment that are insufficient to mediate binding of native RBCs once again promote phagocytosis of bound VaRBCs. Therefore, mild opsonization that may occur in vivo or modifications that may be present on OxRBCs can contribute to the internalization of the bound target cell. Experiments showing that a soluble ligand like the 2.4G2 antibody or a trigger of cytoplasmic signaling like PMA can also promote the phagocytosis of VaRBCs suggest that internalization is initiated by a general signaling event that directs internalization of ligands bound to the PS receptor. Thus, we propose that the exposure of membrane PS that occurs as a consequence of apoptosis or cellular damage is sufficient to explain binding by macrophages but is not sufficient to drive phagocytosis.
In summary, we suggest that phagocytosis of damaged RBCs bound by way of exposed PS requires the cooperation of other membrane receptors to generate a signal for phagocytosis. Oxidation of RBCs must involve many changes in addition to the increase in PS expression on the outer leaflet of the membrane. Lipids undergo oxidation, proteins undergo cross-linking, and the topography of the membrane may be altered in major ways. Further studies will be needed to define exactly which features of the OxRBCs are essential. Whether or not similar considerations apply to apoptotic cells remains to be determined. Competition for binding of apoptotic cells by either PS liposomes or OxLDL is only partial, and it seems unlikely that only one mechanism would have evolved by which damaged and dying cells are recognized and phagocytosed. Most likely there is a redundancy of mechanisms available to support such an important function.
| Selected Abbreviations and Acronyms |
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| Acknowledgments |
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| Footnotes |
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Received March 17, 1997; accepted May 16, 1997.
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