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Serum amyloid P component binds to late apoptotic cells and mediates their uptake by monocyte-derived macrophages.

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ARTHRITIS & RHEUMATISM
Vol. 48, No. 1, January 2003, pp 248–254
DOI 10.1002/art.10737
© 2003, American College of Rheumatology
Serum Amyloid P Component Binds to
Late Apoptotic Cells and Mediates Their Uptake by
Monocyte-Derived Macrophages
Marc Bijl, Gerda Horst, Johan Bijzet, Hendrika Bootsma, Pieter C. Limburg, and
Cees G. M. Kallenberg
Objective. Some pentraxins, such as C-reactive
protein, bind to apoptotic cells and are involved in the
clearance of these cells. We undertook this study to
determine whether serum amyloid P component (SAP; a
pentraxin that, when deficient in mice, results in lupuslike disease) binds to apoptotic cells and to assess the
functional consequences of SAP binding for their phagocytosis by macrophages.
Methods. Human peripheral blood monocytes
were isolated and cultured for 7 days to obtain
monocyte-derived macrophages. Jurkat cells were irradiated with ultraviolet B to induce apoptosis. After 4
hours, a mean ⴞ SEM of 54.0 ⴞ 5.1% of these cells
stained with annexin V and were propidium iodide
negative (early apoptotic [EA] cells). After 24 hours,
77.3 ⴞ 2.7% of cells stained positive with both annexin
V and propidium iodide (late apoptotic [LA] cells or
secondary necrotic cells). EA and LA cells were incubated with fluorescein isothiocyanate–labeled SAP in
the presence or absence of Ca2ⴙ, and binding was
measured by flow cytometry. Phagocytosis was tested by
incubation of macrophages with EA or LA cells in the
presence of normal human serum (NHS) and quantified
as a phagocytosis index (PI; number of Jurkat cells
internalized by 100 macrophages). Experiments were
repeated with SAP-depleted serum and after reconstitution with increasing concentrations of SAP.
Results. The majority of LA cells did bind SAP in
the presence of Ca2ⴙ, whereas EA cells did not. SAP
depletion of NHS resulted in a 50% decrease in the PI
for LA cells, and complete restoration of the PI could be
demonstrated with SAP reconstitution up to 100 ␮g/ml.
SAP depletion had no effect on phagocytosis of EA cells.
Conclusion. SAP binds to LA cells and is involved
in the phagocytosis of these cells by human monocyte–
derived macrophages. This may have consequences for
diseases such as systemic lupus erythematosus, in which
phagocytosis of apoptotic cells is decreased.
Several lines of evidence suggest a role for apoptotic cells in the induction of autoimmunity. First,
intracellular autoantigens are exposed at the outer surface of the cell during the apoptotic process. This may
explain why autoantibodies can develop against these
intracellular antigens (1). Second, injection of large
numbers of apoptotic cells in experimental animal models was shown to induce autoimmunity (2). Based on
these findings, it has been suggested that self-tolerance
is broken by the accumulation of apoptotic cells. Indeed,
in systemic lupus erythematosus (SLE), the prototype of
systemic autoimmune disease, increased levels of apoptotic lymphocytes have been detected in the peripheral
blood (3). This may result from increased production (4)
and/or impaired phagocytosis of apoptotic cells (5).
Phagocytosis of apoptotic cells is a complex process in which many membrane receptors and serum
constituents are involved. Several serum proteins opsonize apoptotic cells, thus facilitating their phagocytosis.
Of these serum proteins, the role of complement components has been elucidated best. C1q-deficient mice
spontaneously develop antinuclear antibodies and glo-
Supported by grant 00-23 from the Jan Kornelis De CockStichting.
Marc Bijl, MD, PhD, Gerda Horst, BSc, Johan Bijzet, BSc,
Hendrika Bootsma, MD, PhD, Pieter C. Limburg, PhD, Cees G. M.
Kallenberg, MD, PhD: University Hospital, Groningen, The Netherlands.
Address correspondence and reprint requests to Marc Bijl,
MD, PhD, Department of Internal Medicine, Division of Clinical
Immunology, University Hospital, PO Box 30.001, 9700 RB Groningen, The Netherlands. E-mail: m.bijl@int.azg.nl.
Submitted for publication February 8, 2002; accepted in
revised form September 30, 2002.
248
SAP AND PHAGOCYTOSIS OF APOPTOTIC CELLS
merulonephritis (6). Interestingly, a striking feature of
glomerulonephritis in these animals was the presence of
increased numbers of apoptotic bodies in their glomeruli, suggesting a role for C1q in the clearance of
apoptotic cells (6). This hypothesis was supported by
findings of additional in vitro studies on phagocytosis of
apoptotic cells. Phagocytosis of apoptotic thymocytes by
inflammatory macrophages was shown to be significantly
reduced in C1q knockout mice (7). In the latter study,
the in vitro phagocytic capacity of 3 patients with C1q
deficiency was also tested. Indeed, a kinetic defect in the
uptake of apoptotic cells was found. C1q-deficient macrophages from these individuals, in autologous serum,
showed a significant reduction in phagocytosis compared
with controls (7). C1q therefore seems essential for the
adequate uptake of apoptotic cells by macrophages.
However, other complement components, such as C3
and C4, and the pentraxins C-reactive protein (CRP),
serum amyloid P component (SAP), and PTX3 also bind
to apoptotic cells and mediate their uptake by macrophages (8,9).
The role of SAP in the handling of apoptotic cells
has been demonstrated in SAP knockout mice. These
animals develop antinuclear antibodies and severe glomerulonephritis, a phenotype resembling human SLE
(10). Since SAP binds to apoptotic cells, we evaluated
whether this binding has functional consequences for the
clearance of apoptotic cells in vitro, using human
monocyte–derived macrophages as phagocytic cells.
MATERIALS AND METHODS
Macrophage culture. Peripheral blood mononuclear
cells were isolated by Lymphoprep density gradient centrifugation from citrated blood. Healthy controls served as donors.
Cells were suspended in medium containing RPMI, gentamicin, and 2% pooled serum at a concentration of 106/ml. Plastic
coverslips (13 mm diameter; Nunc, Roskilde, Denmark) were
placed in a 16 mm–diameter 24-well plate (Costar, Schiphol,
The Netherlands). In every well, 0.5 ml cell suspension was
seeded, and, subsequently, monocytes were allowed to differentiate into macrophages during 7 days at 37°C in a 5% CO2
atmosphere. On day 2 and on day 5, 0.5 ml fresh medium was
added to each well.
Induction and detection of apoptosis. Jurkat cells
suspended in RPMI 1640 supplemented with 13% fetal calf
serum, sodium pyruvate, glutamine, gentamicin, fungizone,
and ␤-mercaptoethanol (BioWhittaker, Verviers, Belgium)
were irradiated with ultraviolet B (UVB; 20W, 170 mJ/cm2)
using a TL12 (Philips, Best, The Netherlands) for 15 minutes
to induce apoptosis. After incubating for 4 hours or 24 hours at
37°C in a 5% CO2 atmosphere, part of the cells were used for
apoptosis detection. For staining, 99 ␮l binding buffer (10 mM
HEPES [pH 7.4], 140 mM NaCl, 5 mM CaCl2), 10 ␮l pro-
249
pidium iodide (10 ␮g/ml; Molecular Probes, Leiden, The
Netherlands), and 1 ␮l fluorescein isothiocyanate (FITC)–
labeled annexin V (Nexins Research, Hoeven, The Netherlands) diluted 1:10 were added. Immediately after incubation
for 10 minutes on ice in the dark, immunofluorescence analysis
was performed on an Epics-Elite equipped with a gated
amplifier (Coulter Electronics, Mijdrecht, The Netherlands).
After 4 hours, 54.0 ⫾ 5.1% (mean ⫾ SEM of 3 experiments) of
Jurkat cells were positive for annexin V and negative for
propidium iodide (early apoptotic [EA] cells), whereas after 24
hours, 77.3 ⫾ 2.7% (3 experiments) of cells stained positive for
both annexin V and propidium iodide (late apoptotic [LA]
cells).
SAP binding to apoptotic cells. SAP was isolated from
pooled human serum. SAP obtained (kindly provided by
B. P. C. Hazenberg, MD, University Hospital, Groningen, The
Netherlands) was 97% pure as confirmed by chromatography.
SAP was labeled with FITC (Pierce, Rockford, IL) according
to the manufacturer’s instructions. Irradiated Jurkat cells (105)
were incubated with FITC-labeled SAP (10 ␮g/ml) in binding
buffer with or without 5 mM CaCl2 for 10 minutes on ice in the
dark. After incubation, immunofluorescence was analyzed by
flow cytometry.
Phagocytosis assay. Irradiated Jurkat cells were
washed 3 times with RPMI and resuspended in RPMI supplemented with 30% fresh human serum at a concentration of 2 ⫻
106/ml. Prior experiments had shown increasing uptake of
apoptotic cells with increasing serum concentrations, and 30%
serum had proved to be a concentration that allowed sufficient
quantitation of uptake (data not shown). Jurkat cell suspension
was added into fresh 24-well plates (1 ml/well). Coverslips with
adherent macrophages were washed with RPMI containing 1%
human serum to remove nonadherent cells and were subsequently transferred into the 24-well plates, where cell interaction was allowed for 30 minutes at 37°C in a 5% CO2
atmosphere. Coverslips were washed gently with 0.4% human
serum albumin (HSA; Central Laboratory of The Netherlands
Red Cross Blood Transfusion Service, Amsterdam, The Netherlands) to remove nonbound cells. For uptake of apoptotic
Jurkat cells, the presence of fresh human serum was obligatory. Without fresh human serum, no internalization could be
detected (data not shown). Experiments were repeated with
SAP-depleted serum (see below) and after reconstitution of
SAP in increasing concentrations of 1 ␮g/ml, 5 ␮g/ml, 10
␮g/ml, 50 ␮g/ml, and 100 ␮g/ml.
Staining procedure and scoring of binding and phagocytosis. To flatten the macrophages, thereby facilitating the
microscopic evaluation of the number of phagocytosed Jurkat
cells, the coverslip was mounted to a “spinning pad” consisting
of 2 cytospin pads (Shandon, Pittsburgh, PA) glued together
(11). From the top pad, 2 squares were cut and coverslips were
placed in the squares. Thereafter, 100 ␮l 4% HSA was added
to the coverslip, and the “spinning pad” was placed within a
24-well lid for centrifugation at 25g for 10 minutes with the lids
mounted at an angle of 100° to the direction of spinning to
ensure quick drying of the coverslip. Coverslips were dried
under air, fixed for 10 minutes with methanol, and stained in
two steps. First, coverslips were stained for 5 minutes with
May-Grünwald staining solution (Merck, Darmstadt, Germany) diluted 1:1 in phosphate buffer (0.069M), followed by
staining for 15 minutes with filtered Giemsa (Merck) diluted
250
BIJL ET AL
Figure 1. Representative figure of annexin V (ANN) and propidium iodide (PI) staining showing serum
amyloid P component (SAP) binding to Jurkat cells 4 hours and 24 hours after ultraviolet B (UVB)
irradiation. Late apoptotic (LA) cells bind SAP. Jurkat cells were irradiated with UVB. Numbers depict
the percentages of cells present in each quadrant. Four hours after irradiation, the majority of cells were
early apoptotic (EA; ANN positive and PI negative) (A), whereas 24 hours after irradiation, most cells
were LA (ANN positive and PI positive) (B). No binding of SAP to EA cells was found (C). In contrast,
the majority (73.7%) of LA cells bound fluorescein isothiocyanate (FITC)–labeled SAP (D).
1:10 in phosphate buffer (0.069M). Excess dye was removed by
2 consecutive incubations in phosphate buffer (0.069M) for 6
minutes. After drying, coverslips were placed upside down with
Depex (BDH Chemicals, Poole, UK) on thin microscopic 24 ⫻
60–mm glasses (Menzel, Braunschweig, Germany).
Preparations were scored at 400⫻ magnification under
regular light microscopy by 2 independent observers. Binding
of apoptotic cells to macrophages was defined as Jurkat cells
that were attached to macrophages but not internalized.
Binding was scored as a binding index (BI; number of Jurkat
cells bound by 100 macrophages). Phagocytosis of apoptotic
Jurkat cells was expressed as a phagocytosis index (PI; number
of Jurkat cells internalized by 100 macrophages). Both the
interobserver and interassay variations were ⬍10% (mean of
10 experiments). All experiments were performed in duplicate.
SAP depletion and enzyme-linked immunosorbent assay (ELISA). For SAP depletion, serum of healthy controls
(normal human serum [NHS]) was brought on an agarose
column enriched with high electroendosmosis agarose (lot no.
AG 0493; FMC Bioproducts, Rockland, ME). Efficiency of
depletion was tested by ELISA. In this assay, Costar plates
(Badhoevedorp, The Netherlands) were coated with monoclonal anti-SAP (Novocastra, Newcastle-upon-Tyne, UK) as
catching antibody. Polyclonal anti-SAP (Dakopatts, Glostrup,
SAP AND PHAGOCYTOSIS OF APOPTOTIC CELLS
251
Figure 2. Ca2⫹-dependent binding of SAP to LA cells. Incubation of EA cells (A) and LA cells (B) with
FITC-labeled SAP was performed in binding buffer without CaCl2 (open pattern) and with CaCl2 added
(solid pattern). No binding of SAP is demonstrated in EA cells, irrespective of the presence of Ca2⫹.
Adding Ca2⫹ to LA cells demonstrates the presence of two cell populations: 62% of cells bind SAP, while
38% do not. See Figure 1 for definitions.
Denmark) was used as detection antibody. Purified SAP was
used as a standard for the assay. The mean ⫾ SEM serum level
of SAP in healthy controls was 27.7 ⫾ 1.0 ␮g/ml. SAP
depletion of ⬎95% was accomplished. To be sure complement
levels were not influenced by SAP depletion, we measured
levels of C3, C4, and C1q after SAP depletion. These levels
were unaltered and were all in the normal range (data not
shown).
Statistical analysis. Statistics were calculated using
GraphPad Prism (version 3.0; GraphPad software, San Diego,
CA). Student’s t-test and one-way analysis of variance with
Bonferroni’s multiple comparison test were applied.
RESULTS
In order to analyze SAP binding to apoptotic
cells, Jurkat cells were irradiated with UVB to induce
apoptosis. After 4 hours, more than one-half of the cells
were EA (Figure 1A). SAP did not bind to these EA
cells (Figure 1C). At this time point, only a minority of
cells were LA. Twenty-four hours after irradiation,
two-thirds of the cells were LA (Figure 1B). Most of
these cells (67.0 ⫾ 3.5%, mean ⫾ SEM of 3 experiments) did bind SAP (Figure 1D). This binding was
shown to be Ca2⫹ dependent, since the absence of Ca2⫹
completely abolished binding of SAP (Figure 2).
In addition, we performed phagocytosis experiments in order to evaluate whether the binding of SAP
influenced the uptake of apoptotic cells by human
monocyte–derived macrophages. Macrophages were in-
cubated with EA cells in NHS either containing SAP or
⬎95% SAP depleted. The level of phagocytosis of EA
cells by macrophages in SAP-depleted serum was comparable with that when cells were incubated in NHS,
reaching mean ⫾ SEM PIs of 44.0 ⫾ 4.0 and 37.0 ⫾ 6.0,
respectively (experiments performed in duplicate).
Experiments using LA cells showed binding of
apoptotic cells to macrophages when incubation had
been performed in NHS irrespective of the presence or
absence of SAP (mean ⫾ SEM BIs 14.0 ⫾ 3.3 and
13.8 ⫾ 1.9, respectively). However, phagocytosis of LA
cells was markedly influenced by the absence of SAP.
Using SAP-depleted serum, the mean ⫾ SEM PI for LA
cells decreased from 38.3 ⫾ 2.9 to 18.7 ⫾ 1.4 (P ⫽ 0.0038
by Student’s t-test) (Figure 3A).
Subsequently, to prove the functional role of SAP
in the uptake of LA cells, we repeated the phagocytosis
experiments using SAP-depleted serum and reconstituted SAP in increasing concentrations. Complete restoration of the PI was demonstrated with SAP reconstitution up to 100 ␮g/ml (Figure 3B).
DISCUSSION
In this study, we demonstrate that SAP binds to
LA cells (or secondary necrotic cells) in a calciumdependent manner. Furthermore, this is the first study to
demonstrate in vitro that this binding has consequences
252
Figure 3. SAP-mediated uptake of LA cells by human monocyte–
derived macrophages. LA cells were incubated for 30 minutes with
monocyte-derived macrophages to allow their binding and internalization. A, Incubation was performed in the presence of 30% normal
human serum (NHS) as well as with SAP-depleted NHS. SAP depletion resulted in a decline in the mean ⫾ SEM phagocytosis index
(number of Jurkat cells internalized by 100 macrophages) from 38.3 ⫾
2.9 to 18.7 ⫾ 1.4 (P ⫽ 0.0038 by Student’s t-test). B, Reconstitution with
purified SAP in increasing concentrations normalized the phagocytosis
index. SAP-depleted NHS and SAP in concentrations of 1 ␮g/ml, 5 ␮g/ml,
and 10 ␮g/ml significantly reduced the phagocytosis index (P ⬍ 0.01, P ⬍
0.05, P ⬍ 0.01, and P ⬍ 0.05, respectively, versus NHS, by Bonferroni
multiple comparison test: P ⫽ 0.0005 versus NHS, by one-way analysis of
variance). Data are based on duplicate experiments. Results are shown as
the mean and SEM. See Figure 1 for other definitions.
for the uptake of LA cells by human monocyte–derived
macrophages. Incubation of macrophages with LA Jurkat cells in the absence of SAP reduced their uptake by
as much as 50%.
BIJL ET AL
SAP belongs to the family of pentraxin proteins.
These proteins are characterized by cyclic pentameric
structure and sequence homology. The interaction of
pentraxins with their respective ligands is calcium dependent. The primary function of SAP is the handling of
DNA, chromatin, and histones in cell nuclei as well as in
solution. As such, SAP seems to prevent the development of autoimmunity, as has recently been reported in
SAP-deficient animals (10). SAP-deficient mice spontaneously develop antinuclear antibodies and glomerulonephritis. It has been suggested that Fc␥ receptor type I
(Fc␥RI), Fc␥RIIa, and Fc␥RIIIb are receptors for SAP
(12). Recently, it has been demonstrated that SAP binds
to phosphatidylethanolamine exposed in flip-flopped
membranes of apoptotic cells in particular (9). Binding
of SAP might result in cell signaling and activation,
followed by the internalization of bound cells. In addition, or in conjunction, mouse SAP has been shown to
induce the production of colony-stimulating factors by
mature macrophages in mice. This mechanism probably
indirectly enhances their phagocytic capacity (13).
Although SAP is not an acute-phase protein in
humans, studies in SAP knockout mice highlighted the
potential role of SAP in the etiopathogenesis of human
autoimmune disease (10). In the prototype of systemic
autoimmune disease, SLE, SAP levels have been measured to analyze whether deficiencies in SAP occur in
SLE patients. Levels of SAP were found to be normal in
sera from lupus patients, irrespective of disease activity
(14).
SAP binds to DNA and chromatin and thereby
solubilizes native chromatin. It seems straightforward to
suggest that SAP plays a role in the clearance of
apoptotic cells, since during the process of apoptosis,
nuclear constituents such as chromatin are expressed on
the cell surface (1). Indeed, in the present study, we
show that SAP binding has functional consequences for
the clearance of LA cells. We found that SAP modulates
the uptake of LA cells by macrophages. Seemingly in
contradiction to our results, no accumulation of apoptotic bodies could be demonstrated in SAP-deficient mice
(10). Furthermore, the autoantibodies produced were
directed against chromatin, histone, and DNA, but not
against extractable nuclear antigens (10). Both findings
provide evidence against a functional role of SAP in the
clearance of apoptotic cells. These discrepancies might
be explained by the preserved ability to internalize
apoptotic cells in a SAP-deficient milieu. Other serum
constituents, such as complement proteins and CRP, are
established opsonizing factors for apoptotic cells. For
the classical complement proteins, there appears to be a
SAP AND PHAGOCYTOSIS OF APOPTOTIC CELLS
hierarchy in the clearance of apoptotic cells, with the
strongest influence of C1q and a lesser dependence on
C4 (7). We show that phagocytosis of apoptotic cells
under conditions of SAP depletion remains possible,
though at decreased levels. The relative phagocytic
defect that occurs in the absence of SAP seems less
pronounced than the defect accomplished through C1q
deficiency, and probably accounts for the absence of
apoptotic bodies in SAP-deficient mice.
Our results are consistent with the current concept of the etiopathogenesis of human SLE. SLE is the
prototype of a systemic autoimmune disease and is
characterized by the presence of antinuclear antibodies,
among which those directed to nucleosomes seem to be
most relevant. Nucleosomes and other nuclear and
cytoplasmic antigens are expressed on the cell surface
during the process of apoptosis. In addition, nucleosomes are released. It has been suggested that the
occurrence of autoantibodies is induced by the accumulation of apoptotic cells, with persistent presentation of
nuclear antigens. Indeed, elevated levels of circulating
nucleosomes can be found in plasma of lupus patients
(15). Furthermore, increased amounts of apoptotic cells
have been demonstrated in the peripheral blood of SLE
patients (3).
Since the clearance of apoptotic cells normally
occurs very rapidly, the presence of apoptotic cells must
reflect disturbances in either the production of apoptotic
cells or their elimination. Increased susceptibility of
peripheral blood lymphocytes to various apoptotic stimuli could be demonstrated in SLE patients and might, in
part, explain the increased production of apoptotic cells
(4). Clearance of apoptotic cells requires their opsonization with complement components such as iC3b, C1q,
and C4 (7,16). A decrease in levels of opsonizing serum
complement components, which is a reflection of complement consumption classically seen in SLE patients,
might result in a decreased capacity for phagocytosis of
apoptotic cells. This, in turn, will result in the persistence
of EA cells and, subsequently, LA cells, especially during
disease activity in which complement consumption is
even more pronounced. We hypothesize that SAP, like
surfactant protein A and the Wiskott-Aldrich syndrome
protein, functions as a salvage protein offering the
immune system a rescue pathway to eliminate LA cells
(17,18). SAP binds to these cells and facilitates their
uptake by macrophages.
In accordance with the concept proposed, a reduced clearance capacity of apoptotic cells in SLE
patients was shown by Herrmann et al (5). In that study,
the expression of the membrane receptors CD14 and
253
CD36 on freshly isolated peripheral blood monocytes of
SLE patients was found to be unaltered compared with
that of healthy controls. This finding suggests that the
impaired phagocytosis cannot be explained by changes
in the membrane expression of CD14 or CD36. Obviously, differences in membrane receptors on other
phagocytes as well as differences in the functionality of
CD14 or CD36 cannot be excluded. Furthermore, many
other membrane receptors on phagocytes, such as the
MER receptor and the phosphatidylserine receptor, are
involved in the internalization of apoptotic cells, and
their role in SLE has not yet been determined. Recently,
it was found in lupus-prone MRL and NZB mice that
these mouse strains did not show intrinsic defects in
phagocytosis of apoptotic cells (19). The above findings
suggest that monocytes and their surface receptors relevant for phagocytosis of apoptotic cells in SLE patients
do not display intrinsic defects. These studies therefore
indirectly support the hypothesis that the reduced clearance capacity in lupus is due to disturbances in the
opsonization of apoptotic cells.
In conclusion, SAP binds to LA cells and facilitates the uptake of these cells by human monocyte–
derived macrophages. We suggest that SAP, next to its
ability to bind to chromatin and regulate its degradation,
functions as a rescue protein for the elimination of
apoptotic cells. In diseases such as SLE, in which the
production of apoptotic cells is increased and their
elimination is hampered, this role of SAP may be of
particular importance. Further studies addressing the
role of pentraxins in the phagocytosis of apoptotic cells
are eagerly awaited.
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