© 1999 American Heart Association, Inc.
Thrombosis |
ß2-Glycoprotein I Promotes the Binding of Anionic Phospholipid Vesicles by Macrophages
From the Divisions of Hematology (P.T., A.L.) and Cardiology (C.R.B.), Department of Internal Medicine, University of Texas Health Sciences Center, Houston.
Correspondence to Perumal Thiagarajan, MD, University of Texas Health Sciences Center, 6431 Fannin St, MSB 5.284, Houston, TX 77030. E-mail perumal{at}heart.med.uth.tmc.edu
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Abstract |
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Abstract—ß2-Glycoprotein I is a single-chain 50-kDa protein that circulates in plasma at a concentration of
200 µg/mL. Its physiological
role remains uncertain, but an important clue is the frequent presence
of antibodies to this protein in patients with recurrent thrombosis. We
have isolated ß2-glycoprotein I and examined
its effect on the binding of phosphatidylserine
(PS) vesicles by human monocyte–derived macrophages and by
phorbol ester–stimulated THP-1 cells.
ß2-Glycoprotein I stimulated the binding of
PS vesicles by these cells in a concentration-dependent manner.
Vesicles containing other anionic phospholipids, such as cardiolipin,
phosphatidic acid, or cardiolipin, inhibited the binding, whereas PC
vesicles had no effect. Platelet-derived microvesicles, which
contain anionic phospholipid on the outer leaflet of their phospholipid
bilayer, also inhibited ß2-glycoprotein
I–dependent binding of anionic phospholipid vesicles. The binding is
associated with incorporation of phospholipid in the cell membrane and
internalization of ß2-glycoprotein I. These
findings suggest a physiological function for
ß2-glycoprotein I in the clearance of
procoagulant anionic phospholipid-containing cell surfaces from
the circulation.
Key Words: lupus anticoagulant • antiphospholipid antibody • ß2-glycoprotein I • anionic phospholipid vesicles
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Introduction |
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ß2-Glycoprotein I is a single-chain 50-kDa lipid-binding serum glycoprotein first identified in 1961.1 The plasma concentration of this glycoprotein is
4 µmol/L (200 µg/mL), of
which one third is bound to lipoproteins.2 Because of its
association with lipoprotein fractions,
ß2-glycoprotein I is also referred to as
apolipoprotein H. Human ß2-glycoprotein I was
completely sequenced and cloned, and the gene has been localized to
chromosome 17.3 4 5
ß2-Glycoprotein I is a member of the
so-called "complement control protein" (CCP)
superfamily,6 7 whose members are identified by the
presence of 
1 repeats of 60 amino acid sequences characterized by
a relatively invariant arrangement of 2 disulfide bonds and a number of
other highly conserved residues.
ß2-Glycoprotein I is made up of 5 complement
control protein repeats, the fifth of which has a relatively unusual
pattern of 3 disulfide bridges and contains a positively charged
sequence, CKNKEKKC, that has been shown to be a binding site for
anionic phospholipid.8 The physiological role of ß2-glycoprotein I remains uncertain. It has been reported to bind negatively charged surfaces, including anionic phospholipid vesicles,9 platelets,10 platelet-derived microparticles,11 and apoptotic cells.12 Binding is accompanied in vitro by inhibition of phospholipid-dependent coagulation tests.13 Here, we show that ß2-glycoprotein I promotes the binding and internalization of anionic phospholipid vesicles by macrophages.
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Methods |
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RPMI medium 1640, cholesterol, and phorbol 12-myristate 13-acetate (PMA) were obtained from Sigma Chemical Co. Bovine brain phosphatidylserine (PS), egg phosphatidylcholine (PC), heart cardiolipin, liver phosphatidylinositol, liver phosphatidylethanolamine, and N-[4-nitro-2-oxa-1,3-diazole]-L-
-phosphatidylcholine
(NBD-PC) were obtained from Avanti Polar Lipids. Butylated
hydroxytoluene was added to a final concentration of 100
µmol/mol phospholipid. Carrier-free [125I]NaI
was obtained from Amersham Corp. Iodogen was purchased from Pierce
Chemical Co.
Isolation of ß2-Glycoprotein I
ß2-Glycoprotein I was
isolated from normal citrated plasma as described
previously,14 with some modifications. Plasma (100 mL) was
mixed with 2.5 mL 70% (vol/vol) perchloric acid, stirred gently at
4°C for 15 minutes, and centrifuged at 13 000g
for 15 minutes at 4°C. After the supernatant was neutralized to pH
7.0 with 12.5 mol/L NaOH, 43 g of ammonium sulfate powder was
added, and the mixture was stirred at 4°C for 30 minutes. After
centrifugation at 13 000g for 15 minutes at
4°C, the precipitate was dissolved in 0.03 mol/L NaCl, 0.02 mol/L
Tris-HCl, pH 8.0, and dialyzed against the same buffer. The sample was
applied to a column of heparin-Sepharose (2x15 cm) that was washed
sequentially with 400 mL 0.05 mol/L NaCl, 0.02 mol/L Tris, pH 8.0, and
400 mL 0.15 mol/L NaCl, 0.02 mol/L Tris, pH 8.0, and then eluted with
0.35 mol/L NaCl, 0.02 mol/L Tris, pH 8.0. The
ß2-glycoprotein I–containing peak
was dialyzed against a buffer containing 0.05 mol/L HEPES, 0.05 mol/L
NaCl, pH 7.0, applied to a Mono S column (Pharmacia Biotech Inc), and
eluted with 0.05 to 0.5 mol/L salt gradient in the same buffer. The
ß2-glycoprotein I peak was
collected and dialyzed against HBS (0.15 mol/L NaCl, 0.02 mol/L HEPES,
pH 7.4). ß2-Glycoprotein I was
iodinated with [125I]NaI by the
Iodogen method.15
Phospholipid Vesicles
Phospholipid-cholesterol vesicles were prepared with
a molar ratio of phospholipid to cholesterol of 1:0.75. The
phospholipid used was either 100% PS or PC. When mixed vesicles were
prepared, the molar concentration of phospholipid was the same with
different proportions of PS and PC. Vesicles were prepared with a
nonexchangeable tracer, [3H]cholesteryl
hexadecyl ether (Amersham Co), to quantify the binding of
phospholipid.16 Phospholipid and cholesterol
were dissolved in chloroform and evaporated to dryness in a glass
ampoule with a gentle stream of dry nitrogen and suspended in 5 mL of
buffer (0.15 mol/L NaCl, 0.01 mol/L HEPES, pH 7.4). The suspension was
deaerated by bubbling with dry nitrogen for 15 minutes. The ampoule was
flame-sealed and placed in a water bath, and the phospholipid
suspension was emulsified by sonication (Heat System Ultrasonics, Inc)
for 45 minutes, the temperature being maintained at 20°C to 25°C by
the addition of ice to the bath. The phospholipid vesicles were then
passed through a 0.2-µm filter (Gelman Sciences) and stored at 4°C.
The phospholipid vesicles were examined by electron microscopy and
negative staining with uranyl acetate and shown to be almost
exclusively unilamellar vesicles <200 nm in diameter. Lipid
peroxidation products in the phospholipid preparations were
measured by the thiobarbituric acid method as described
before.17 The lipid peroxide contents were <1.07±0.03
(n=3) nmol/mg of phospholipid. Fluorescent vesicles had the
same lipid composition with the addition of NBD-PC (2% of the total
phospholipid, wt/wt) but without the tracer.
Cell Lines and Macrophages
THP-1 cells obtained from the American Type Culture Collection
were grown in tissue culture flasks under 5% CO2
at 37°C in RPMI 1640 medium containing 10%
heat-inactivated FCS. The cells were treated with PMA (100
nmol/L), plated in 24-well plates (Costar)
(2x106 cells/plate), and allowed to
differentiate for 72 hours. Human monocyte–derived tissue
macrophages were prepared by culturing peripheral
blood monocytes isolated by the Ficoll-Hypaque gradient method, as
previously described.18 Platelet-derived microvesicles
were prepared as described before.19 20
Phospholipid Binding Assay
Tissue culture wells containing 2x106
adherent, differentiated THP-1 cells or 0.5x106
monocyte-derived macrophages were washed in PBS and replaced
with serum-free Medium 199 containing various concentrations of
[3H]cholesterol-labeled
phospholipid vesicles. The medium contains 1 mmol/L
Ca2+.
ß2-Glycoprotein I was added and
incubated at 37°C for 4 hours. At the end of the incubation period,
the cells were rapidly washed 6 times in serum-free Medium 199. The
cells were solubilized by incubation in a 200-µL volume of 2% SDS
for 20 minutes. The cell-associated radioactivity was counted in a
scintillation counter. To correct for nonspecific binding, in each
experiment, parallel wells containing tissue culture medium without
cells were incubated with
ß2-glycoprotein I and anionic
phospholipid vesicles, and the binding was subtracted from total
binding.
Flow Cytometric Analysis of Incorporation of
Phospholipid
Phorbol ester–stimulated THP-1 cells were incubated with
fluorescent-PS vesicles (100 µmol/L) in serum-free
medium in the presence or absence of
ß2-glycoprotein I (100
µmol/L). After 4 hours of incubation at 37°C, the cell layers were
washed in serum-free medium and trypsinized. The single-cell
suspensions of THP-1 cells were analyzed for cell-associated
fluorescence by flow cytometry.
Internalization of 125I-Labeled
ß2-Glycoprotein I
THP-1 cells (15x106) were seeded in 60-mm
tissue culture dishes (Corning Glass Works) in the presence of 100
nmol/L PMA. Three days later, cell layers were washed 3 times in
serum-free medium, and 1 mL of medium containing 3% BSA and 400 nmol/L
125I-ß2-glycoprotein
I was added. After incubation for 1 hour at 37°C, the
overlying medium was removed, and the cells were incubated for 30
minutes at 4°C in tissue culture medium containing 0.25% Pronase,
which removes cell surface ligands and also detaches the cells. The
detached cells were separated from the medium by
centrifugation and washed 3 times. Radioactivity
associated with the cell pellet (internalized Pronace-insensitive
ligand) was determined in a gamma counter.
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Results |
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Effect of ß2-Glycoprotein I on the Binding of Anionic Phospholipid Vesicles
As shown in Figure 1A
, when phorbol
ester–stimulated THP-1 cells were incubated with PS vesicles (75
µmol/L) at 37°C in the presence of
ß2-glycoprotein I, the vesicle
binding was linear for 2 hours and reached saturation at 2.5 to 3
hours. In the absence of
ß2-glycoprotein I, the vesicle
binding was decreased by 90%. Binding was dependent on the
concentrations of both PS vesicles (Figure 1B) and
ß2-glycoprotein I (Figure 1C) and was optimal at 150 µmol/L of PS and at 100
µg/mL of ß2-glycoprotein I. The
effect of ß2-glycoprotein I on PS
vesicle binding was temperature-dependent (Figure 1D): PS
binding at 4°C was 20% of the binding at 37°C. Binding of PC
vesicles by THP-1 cells under the same conditions was 20-fold less, and
ß2-glycoprotein I did not have any
stimulatory effect on the binding. When peripheral blood
monocyte-derived macrophages were incubated with PS, a similar
ß2-glycoprotein I–dependent
binding of anionic phospholipid vesicles was seen (Figure 2). The
ß2-glycoprotein I–dependent
binding of PS vesicles to THP-1 cells is proportional to the
concentration of PS in the vesicles (Figure 3). Binding increases when the PS content
is >10% of total phospholipids.
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) or absence (•) of 100 µg/mL of
ß2-glycoprotein I, and the cell-bound
radioactivity was determined after washing. B, Concentration dependence
of PS vesicle binding. The cells were incubated in the presence (
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Effect of Phospholipid Composition on
ß2-Glycoprotein I–Dependent Binding of
Anionic Phospholipid Vesicles
Anionic phospholipid vesicles containing PS, phosphatidic acid, or
cardiolipin (Figure 4) inhibited
binding of the radiolabeled PS vesicles, whereas neutral or
zwitterionic phospholipid vesicles composed of PC (Figure 4),
sphingomyelin, or phosphatidylethanolamine (data not shown) had no
effect. Incorporation of dicetyl phosphate or stearylamine to give a
net negative or positive charge to the phospholipid vesicles,
respectively, had no significant effect on the binding, suggesting that
charge alone does not confer
ß2-glycoprotein I–dependent
binding (data not shown). Platelet-derived microvesicles have
previously been shown to contain anionic phospholipid on their outer
surface.20 Inhibition of
ß2-glycoprotein I–dependent
binding of PS vesicles is consistent with these observations
(Figure 4).
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ß2-Glycoprotein I–Dependent
Incorporation of Anionic Phospholipid
To determine whether the enhanced binding of anionic phospholipid
vesicles to macrophage membranes is associated with
incorporation of phospholipids in the membrane, fluorescent PS
vesicles containing NBD-PC as fluorescent tracer were incubated
with phorbol ester–stimulated THP-1 cells in the presence of
ß2-glycoprotein I. The cell-bound
phospholipid vesicles were analyzed by flow cytometry. The
presence of ß2-glycoprotein I
resulted in increased incorporation of PS-containing
fluorescent phospholipids (Figure 5). No significant effect of
ß2-glycoprotein I was seen when
cells were incubated with PC-containing vesicles.
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PS Vesicle–Dependent Internalization of
ß2-Glycoprotein I by THP-1 Cells
To determine whether incubation of
ß2-glycoprotein I with PS vesicles
results in the internalization of
ß2-glycoprotein I,
125I-labeled
ß2-glycoprotein I (400 nmol/L) was
incubated with phorbol ester–stimulated THP-1 cells in the presence of
PS or PC vesicles. There was a dose-dependent increase in the
internalization of ß2-glycoprotein
I by PS vesicles, whereas PC vesicles had no significant effect (Figure 6).
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Discussion |
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The experiments reported here show that ß2-glycoprotein I promotes the binding of anionic phospholipid vesicles to macrophages. This effect is saturable, temperature-dependent, and specific for anionic phospholipids. Cell surfaces containing anionic phospholipids, such as platelet-derived microvesicles, inhibit this binding. These studies suggest a physiological function for ß2-glycoprotein I in the clearance of anionic phospholipid-containing procoagulant surfaces from the circulation. The complex of anionic phospholipid vesicles and ß2-glycoprotein I is recognized by a putative cell surface receptor on macrophages or possibly other cells. These complexes are taken into a receptor-mediated pathway, and this may play a role in the removal of procoagulant anionic phospholipid surfaces from the circulation. Wurm et al21 showed that infusion of ß2-glycoprotein I in rats results in an accelerated clearance of triglyceride-rich vesicles from the circulation, and Chonn et al22 showed ß2-glycoprotein I–dependent clearance of anionic phospholipid vesicles in mice. Our results showing that ß2-glycoprotein I enhances the binding of anionic phospholipid to macrophages are consistent with these reports.
Nishikawa et al23 first reported in 1990 that macrophage scavenger receptor mediates the binding of anionic phospholipid to mouse peritoneal macrophages. However, using Chinese hamster ovary cells transfected with class A bovine macrophage scavenger receptor, Lee et al24 could not demonstrate this effect. The possible role of ß2-glycoprotein I was not studied, and it is possible that the presence of ß2-glycoprotein I might have given these conflicting results. Recently, additional receptors, distinct from the type A scavenger receptors that bind oxidized LDL and PS vesicles, have been identified.25 26 27 At least 1 of these receptors also binds oxidized red blood cells and apoptotic cells by a PS-dependent mechanism.28 The precise identification of the receptor(s) that mediates ß2-glycoprotein I–dependent binding of anionic phospholipid vesicles will require transfection studies with these candidate receptors.
Decreased levels of ß2-glycoprotein I have been reported in disseminated intravascular coagulation, a condition associated with platelet activation and generation of microvesicles in vivo.29 30 In addition, patients with antiphospholipid antibody syndrome have in their serum immunoglobulins that react with anionic phospholipids in a variety of immunological assays.31 The precise antigenic target of antiphospholipid antibodies, whether neoepitopes induced in protein, such as ß2-glycoprotein I, after phospholipid or surface binding or a complex conformational epitope consisting of protein and phospholipid, has not been resolved and is a subject of controversy.9 31 32 33 34 At least some of these antibodies recognize a complex epitope consisting of anionic phospholipid bound to ß2-glycoprotein I and other phospholipid-binding proteins.31 32 These antibodies may impair the clearance of ß2-glycoprotein I–dependent binding of anionic phospholipid vesicles by interfering with the binding and/or internalization of procoagulant anionic phospholipid surfaces of activated platelets and apoptotic cells, allowing prolonged survival of procoagulant anionic phospholipid vesicles in the circulation. In fact, increased levels of platelet-derived microvesicles have been reported in the plasma of patients with the antiphospholipid antibody syndrome.35 However, hereditary deficiency of ß2-glycoprotein I does not appear to be associated with risk of a hypercoagulable state.36 Thrombosis is a complex multigene phenotype. Because of the large number of genes that influence this phenotype, teasing out the role of the ß2-glycoprotein I locus will be difficult. One would expect that ß2-glycoprotein I deficiency would contribute to a prothrombotic tendency when it is coincident with other genetic risks for thrombosis, for example, heterozygosity for factor V Leiden. When these studies were in progress, Balasubramanian et al37 reported that human ß2-glycoprotein I did not stimulate the uptake of PS vesicles by mouse macrophages. However, the concentration of ß2-glycoprotein I used in that study (5 µg/mL) was at least 10 times lower than the physiological concentration. Furthermore, species differences could account for the differences. Manfredi et al38 did not find a significant role for ß2-glycoprotein I in the phagocytosis of apoptotic T cells by macrophages. They used 10% serum as a source of ß2-glycoprotein I, a suboptimal concentration for enhanced binding. Furthermore, the extent of PS exposure may vary under different conditions, giving rise to negative effects.
In conclusion, our results show that ß2-glycoprotein I promotes the binding of anionic phospholipid-containing vesicles by a macrophage. This mechanism may have a physiological role in removing procoagulant phospholipid vesicles or cell fragments from circulation.
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Acknowledgments |
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This work was supported by NIH grants HL-40860, HL-50100, and HL-50653 and a Grant-in-Aid from the American Heart Association. We thank Dr I. Jialal for thiobarbituric acid assays and Dr Jose Lopez for critical review of the manuscript.
Received August 18, 1998; accepted March 26, 1999.
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