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*
Laboratory for Cellular and Molecular Immunology, Department of Medicine, Hadassah University Hospital, Jerusalem, Israel;
Sourasky Medical Center, Tel-Aviv, Israel; and
Immunology Unit, Bney-Zion Hospital, Haifa, Israel
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The mechanisms whereby apoptotic cells are identified, removed, and
degraded by phagocytes in mammalian cells are not completely
understood. However, some progress in elucidating them has been made in
the nematode, Caenorhabditis elegans, and in human and
murine systems. Recent studies showed several receptors and molecules
as being important in the uptake of apoptotic cells in mammals
(7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19). The complement system was found to have a role in
opsonization and interaction with apoptotic cells (17, 20)
and in apoptosis (21). Two important families of receptors
reported to date in mammals are the scavenger receptors (10, 11, 12, 14, 22) and the integrins (8, 16, 17, 18).
3, 5, and
2 integrins were shown to have a role in
mediating the interaction between apoptotic cells and macrophages or
dendritic cells. We had recently shown that apoptotic cells can
partially activate the complement system leading to opsonization of
apoptotic cells by iC3b and binding or phagocytosis via the integrin
receptors of the 2 family, CD11b/CD18 and
CD11c/CD18 (17). In the present in vitro study, we
examined the interaction of heterologous apoptotic murine thymocytes
opsonized by homologous iC3b by macrophages from SLE patients. In this
unique in vitro system, iC3b opsonization is crucial for association
between murine apoptotic cells and human macrophages, and the role of
known important receptors for uptake of apoptotic cells such as
v3, CD14, CD36, and
phosphatidylserine receptor is not dominant. We show that a decrease in
interaction characterized most patients with SLE and was associated
with accelerated Fas-mediated apoptosis of monocytes and maturing
macrophages.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Forty SLE patients who fulfilled the revised American Rheumatism Association criteria for SLE from an outpatient rheumatology clinic participated in the current study, which was approved by the institutional ethics committee, Ministry of Health, Jerusalem, Israel. Patients on cytotoxic drug therapy, cyclophosphamide, azathyoprine, or methotrexate, as well as those under treatment with prednisone >30 mg/day were excluded. After signing an informed consent, the patients were evaluated for SLE disease activity index and 30–45 ml of peripheral venous blood was drawn. Forty sex- and age-matched (±4.2 years) healthy controls were recruited from the hospital staff on the same day, and 26 sex- and age-matched (±3.5 years) patients with rheumatoid arthritis (RA) comprised the disease control group.
Cell isolation and culture
Human mononuclear cells were isolated from heparinized peripheral blood by density gradient centrifugation and adherence to plastic (17), from which 107/ml mononuclears were plated, unless indicated otherwise. The cells were cultured with 10% AB human serum (Sigma-Aldrich, St. Louis, MO) in Iscove’s medium (Biological Industries, Kibbutz Bet-Haemek, Israel). After 7 days of culture, the cells matured into macrophages (>95% pure, as assessed by CD14 staining) and were used for interaction assays.
Apoptosis
Apoptosis of thymocytes from BALB/c or C3H/SnJ was induced by irradiation (600 rad) or serum deprivation (3). Apoptosis was confirmed by morphology as well as by two flow cytometry methods: propidium iodide (PI) staining of fragmented DNA (23) and phosphatidylserine staining by annexin V conjugated to FITC (24) (R&D Systems, Minneapolis, MN). More than 70% of the cells were apoptotic and had an intact membrane, as evidenced by 0–2% trypan blue-positive cells and 2–4% PI-positive cells. Apoptosis of monocytes was assessed both by staining of fragmented DNA following 20 min of trypsin-EDTA treatment and by 24-h interval counting of marked areas on the slides. Triplicates of marked areas contained at least 200 adhered monocytes at day 0. Eight SLE patients (20%) had low lymphocyte counts, and two (5%) had low monocyte counts on the day of blood donation. However, survival counting was started 1 h after adherence and applied to adhered monocytes only.
Interaction of apoptotic cells with macrophages
Interaction assays were performed simultaneously on peripheral
blood monocyte-derived macrophages obtained from healthy individuals
and the SLE study patients, and when possible simultaneously with
patients with RA, as described elsewhere (17). Briefly, to
examine the behavior of the iC3b-opsonized apoptotic cells and the
complement receptors, CD11b/CD18 and CD11c/CD18, specifically, a
heterologous system was used with murine apoptotic thymocytes and human
monocyte-derived macrophages. In this system, >90% of apoptotic cells
are opsonized by iC3b and interact via CD11b/CD18 and CD11c/CD18
(17). Macrophages (
25,000) were incubated for 1 h
at 37°C/5% CO2 with 106
apoptotic cells (approximate ratio of 1:40) in triplicate in the
presence or absence of 10% AB serum (Sigma-Aldrich) or
complement-deficient sera (Sigma-Aldrich). The interaction was stopped
by dipping the slides in ice-cold PBS to remove the nonbound apoptotic
cells. In some experiments, we added trypsin-EDTA (Biological
Industries) for 20 min and cytospinned the cells. The slides were fixed
with 100% ethanol and Wright stained. The proportion of free and
macrophage-bound target cells was established by counting 400 monolayer
cells per test sample. The interaction index was defined as the number
of apoptotic thymocytes that were attached to 100 macrophages. The term
"interaction index" was used to describe association between
apoptotic cells and macrophages without further kinetic evidences for
clearance. Some authors used trypsin-EDTA to distinguish between
binding or tethering and phagocytosis. Following the interaction assay,
we added to several samples trypsin-EDTA for 20 min and reevaluated
interaction index. We observed a 30–40% decrease in the index,
suggesting that >60% of opsonized apoptotic cells were internalized
or trypsin resistant bound to macrophages. However, we were not sure
that this method distinguishes between bound or internalized apoptotic
cells, so it was not applied to the whole study. Accuracy was
considerably enhanced by video imaging the high-power microscopic
fields. Two independent observers who were blinded to conditions
evaluated the samples. Receptor-blocking reagents were added before the
incubation with apoptotic cells in some experiments. Interaction index
was also evaluated as a function of macrophage densities. Although
plated monocyte numbers were comparable, the actual numbers per one
square millimeter could vary according to the area chosen (usually
between 200 and 300 monocytes at 1 h after adherence). Absolute
numbers could have been misleading and were used only for single donor
evaluation. To compare the survival rate between different donors, we
used percentage density of macrophages instead of total numbers. For
example, if donor A and donor B had 100 cells per one square millimeter
by day 7, their mean percentage density would depend on their number at
day 0. If, for instance, by day 0 donor A had 200 cells per one square
millimeter and donor B had 300, their mean percentage density at day 7
would be 50 and 33% for A and B, respectively. The term "mean" was
used because we averaged three counts.
Validation of interaction index was obtained by staining apoptotic cells with PKH-27 (Sigma-Aldrich), and using flow cytometry for measuring uptake of apoptotic cells (16). Chinese hamster ovary (CHO) transfected with CD11b/CD18 (25) was used to further show the role of CD11b/CD18 in this system (17).
Blocking mAbs and peptides
The following reagents were used to determine the relative
contribution of each receptor: macrophage lectin receptor was inhibited
by 20 mM N-acetyl glucosamine (Sigma-Aldrich);
V3, the vitronectin
receptor, was blocked with 2 mM tetra peptide RGDS
(Sigma-Aldrich) or control tetra peptide RGES (Sigma-Aldrich) for 15
min/37°C/5% CO2. CD36 was blocked with the
anti-CD36 mAb (FA6, kindly provided by R. Silverstein, Cornell
University, New York, NY) or an isotype-matched control Ab. CD14
was blocked with anti-61D3 (kindly provided by C. Gregory,
Birmingham, U.K) or anti-CD14 (63D3, control mAb; American
Type Culture Collection, Manassas, VA), and the complement receptors,
CD11b/CD18 and CD11c/CD18, were blocked by mAbs, anti-CD11b/CD18 (I
domain, MN-41, a gift from V. Vetvicka, Louisville, KY), and
anti-CD11c/CD18 (anti-CD11c; Sigma-Aldrich). Soluble Fas/Fc
chimera (R&D Systems) and Fc fragment (Chemicon International,
Temecula, CA) were used for blocking Fas-mediated apoptosis.
Flow cytometry
Mononuclear cells were gated using forward and side scatter to distinguish between lymphocytes and monocytes. The gating was verified by using CD14-APC (IQ Products, Groningen, The Netherlands) staining for monocytes. Apoptosis was determined using PI and hypodiploid staining or annexin V FITC and PI for nonfixed cells. Flow cytometry analysis was performed on a FACScan (BD Biosciences, Mountain View, CA).
Statistics
Experiments were performed in duplicate or triplicate, and average results were compared among healthy donors, SLE patients, and patients with RA. Student’s t test was used to compare results.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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As shown in Fig. 1
A,
complement factors were required for interaction of >90% of apoptotic
thymocytes with human macrophages. More than 90% of the apoptotic
thymocytes were coated with iC3b (data not shown). The interaction
index of healthy individuals that had been 541 ± 74 in the
presence of human serum, decreased dramatically both by heat
inactivation and by C1q, C2, C3, and C4 depletion. Moreover, adding the
missing factors, but not C9, restored the uptake. To verify that
CD11b/CD18 and CD11c/CD18 were important in the interaction with
iC3b-opsonized cells, 20 mM N-acetyl glucosamine and mAbs to
CD14 (61D3), CD36, CD11b/CD18, CD11c/CD18, and RGDS, inhibitory
tetra peptide to vitronectin receptor, were examined for
inhibition (Fig. 1B). Significant inhibition of interaction
was seen by using mAbs to CD11b/CD18 and CD11c/CD18
(p < 0.001 and p < 0.006,
respectively). Mild inhibition (p < 0.08) was
seen using RGD peptide. To further establish the role of complement
receptors in this system, a CHO cell line transfected with human
CD11b/CD18 was examined for uptake of iC3b-opsonized apoptotic murine
thymocytes. Adhered cells with no transfection showed an interaction
index of 3 ± 1, whereas transfected CHO cells had 166 ± 19
(p < 0.00001). Taken together, these results
confirm that in this assay the complement system is activated by
apoptotic cells and represents the major factor that allows interaction
between macrophages and heterologous apoptotic cells.
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Of 40 blood samples from SLE patients, 30 interaction assays were
performed using monocyte-derived macrophages from SLE patients. The
assays were performed simultaneously with 30 healthy and disease (RA)
controls. Eight additional sets were excluded due to an extremely low
survival rate of macrophages from SLE patients (see further), while
another two were excluded due to infection. As shown in Fig. 2, the interaction index of apoptotic
cells with human monocyte-derived macrophages was significantly lower
in patients with SLE and was, on average, 71% ± 37 of the healthy
controls (p < 0.002) and 69% ± 35 of the RA
patients (p < 0.007). The SLE patients
displayed a wide range of interaction index 14–145(14–145) when compared
with RA patients 70–133(70–133). These results indicate that at least
one-third of SLE patients had specific impairment in interaction of
iC3b-opsonized apoptotic cells with macrophages. No significant
differences were noted between the subgroup with severe impairment and
the rest of the group with regard to SLE disease activity index
or disease duration (data not shown).
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Although the same number of mononuclear cells from SLE, RA, and
healthy donors was plated on slides, the slides from SLE patients
contained fewer macrophages per area when compared with healthy
individuals. To further explore this observation, 19 SLE patients were
evaluated for survival and apoptosis. The numbers of monocyte-derived
macrophages per one square millimeter were significantly reduced in SLE
patients (p < 0.01) (Fig. 3). However, two subpopulations could be
identified, and 11 of 19 counted (58%) SLE patients had significantly
reduced survival, while the rest were in normal range. In addition,
eight of 38 patients with SLE and none with RA were excluded from the
assays due to extremely reduced survival and low numbers of macrophages
at day 7. Taken together, at day 7 in culture, approximately two-thirds
of SLE patients had decreased survival of adherent monocyte-derived
macrophages.
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To verify that the decreased numbers of macrophages were due to
accelerated apoptosis, we examined first the percentage of apoptosis in
freshly isolated monocytes. An increased apoptosis rate of freshly
isolated lymphocytes and mononuclear cells had been reported by others
(26, 27). However, no data were provided regarding freshly
isolated monocytes in these studies. To determine whether the decreased
numbers of monocyte-derived macrophages are due to accelerated
apoptosis of freshly isolated monocytes, we examined 14 samples from
SLE patients and compared them with healthy and RA controls. As shown
in Fig. 4A, apoptosis of
monocytes was significantly increased in the SLE patients when compared
with healthy (p < 0.001) or RA
(p < 0.004) controls. Furthermore, monocyte
apoptosis was much more significant than lymphocytes, as shown in Fig. 4B. The next question to be examined was whether accelerated
apoptosis characterizes freshly isolated monocytes only or is seen
during macrophage maturation as well. We tested the rate of apoptosis
of the monocytes upon their maturation to macrophages on a daily basis.
As shown in Fig. 5A, the
percentage of apoptosis was significantly (p <
0.04) increased in patients with SLE during monocyte/macrophage
maturation. Thus, in patients with SLE, both freshly isolated monocytes
and adhered monocytes that mature to macrophages show increased rate of
apoptosis. Since apoptosis of monocytes during maturation to
macrophages was shown to be Fas (CD95) dependent (28, 29),
we next asked whether the acceleration in apoptosis of monocytes in
patients with SLE is Fas dependent. As shown in Fig. 5B,
monocytes exposed to recombinant human Fas/Fc chimera, but not to
control, had restored numbers of macrophages at day 7.
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No significant differences were seen in the expression of
CD11b/CD18 or CD11c/CD18 on macrophages from SLE patients when compared
with healthy controls (data not shown). Although the impaired clearance
could have been due to intrinsic malfunction of the receptors, we
examined the role of macrophage density in relation to interaction with
apoptotic cells. Our assumption was that the reduction of macrophages
should not, by itself, have changed the interaction index, since
it expresses the ability of the remaining macrophages only to
bind/engulf apoptotic cells. To verify that the increased death of
monocytes is not a major contributor to the decreased uptake observed
in the remaining macrophages, we prepared gradually decreasing
densities of macrophages from healthy individuals and evaluated their
interaction index as an expression of their density (Fig. 6A). We were surprised to see
that a decreased density by itself caused significant decreased uptake
of apoptotic cells, meaning that the function of the remaining
macrophages was altered by the absence of other macrophages that
underwent apoptosis. This is further emphasized by the fact that the
number of apoptotic cells was not reduced, allowing higher ratios of
apoptotic cells:macrophages. To further examine whether the low density
of monocyte-derived macrophages in SLE patients influences the altered
uptake in these patients, we used macrophages with added Fas/Fc chimera
at day 0 for evaluation of interaction index. As shown in Fig. 6B, a dramatic improvement of the impaired interaction index
was observed when macrophages were in densities similar to those of
healthy controls (p < 0.002). We performed a
similar set of experiments in which we plated at day 0 up to 80%
higher concentrations of monocytes from patients with known accelerated
apoptosis. On day 7, just before the phagocytic assay, we counted
macrophages per area and included patients with ±15% of densities of
healthy donors and compared them with both healthy donors and their own
macrophages being plated at normal densities. Again, the interaction
index improved dramatically (data not shown). We named this phenomenon
a loss of community effect, indicating that macrophages need to be in a
close contact with one another to better bind/engulf apoptotic
cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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v3, CD14, CD36, and
phosphatidylserine receptor was not examined. In this system, we
demonstrated that accelerated apoptosis of both freshly isolated
monocytes and monocytes maturing to macrophages was associated with in
vitro impairment in interaction between apoptotic cells and
macrophages. The accelerated apoptosis dramatically influenced the
efficiency of clearance of the remaining macrophages. Indeed, upon
restoration of the numbers of macrophages per one square millimeter,
many SLE macrophages were able to interact with apoptotic cells
similarly to normal and RA controls. Interestingly, a community effect
is seen both in patients with SLE and healthy controls and may explain
conflicting results reported from different studies examining uptake of
apoptotic cells without careful comparison of their densities. A loss
of community effect could be secondary to physical contact by
pseudopods or ingredients of the microenvironment like cytokines,
chemokines, or serum proteins (31). A community effect may
contribute to each step of migration toward an apoptotic cell, i.e.,
protrusion, adhesion, traction, and deadhesion (37).
The next question that arises is why do monocytes/macrophages from SLE
patients have accelerated apoptosis? Sera from SLE patients were
suggested to inhibit adhered monocyte motility and, as a consequence,
decreased phagocytosis of yeast (38) or to induce
apoptosis to monocytes (39). In this study, monocytes were
maturing in the presence of AB serum from healthy donors for 1 wk, and
the interaction assays were done in the presence of AB serum.
Furthermore, the factors suggested to mediate these effects were low
complement factors and the presence of autoantibodies or immune
complexes, none of which was present in the serum used. Another
possibility is expression of proapoptotic molecules following
activation, as suggested for lymphocytes (40). In contrast
to ced-9 in C. elegans, mammalian homologues have
both anti- and proapoptotic genes (inhibitors such as Bcl-2 and
promoters such as Bax), and proapoptotic equilibrium of
bcl-2 family may appear in lymphocytes from SLE patients
(41, 42, 43). Alternatively, the withdrawal of growth factors
and cytokines may have a paracrine and/or autocrine role, as shown for
lymphocytes (43, 44). However, recent reports explored
death mechanisms appearing specifically in monocytes and monocytes
maturing to macrophages in healthy individuals. Human monocytes undergo
spontaneous apoptosis due to Fas upon being cultured by an autocrine or
paracrine pathway (28, 29). The death receptor, Fas, a
member of the TNFR family, efficiently activates caspases and induces
apoptosis following binding and trimerization. Fas-Ig fusion protein,
an antagonistic anti-Fas mAb, and a rabbit anti-Fas ligand Ab
all greatly reduced the onset of apoptosis (29). In this
study, adding soluble Fas avoided accelerated apoptosis of monocytes,
indicating that the accelerated apoptosis is at least partially Fas
mediated and may be related to activation-induced cell death
(45). Acceleration of additional non-Fas-dependent
apoptosis pathways was not excluded in this study. We observed in a few
patients severe acceleration in apoptosis during maturation, but most
death occurred at days 0–2, and macrophages that survived showed
normal morphology. The reason that the vast majority of death
occurred during the first days of maturation may be related to the late
expression of Fas-associated death domain-like IL-1-converting
enzyme-inhibitory protein (FLIP) activity (46).
Monocyte-derived macrophages, despite the expression of both Fas and
Fas ligand, do not undergo spontaneous apoptosis and are not sensitive
to stimulation by an agonistic anti-Fas IgM. Recently, a protective
mechanism in monocyte-derived macrophages that exist at a site
downstream of the receptor-ligand interaction was identified. Monocyte
differentiation into macrophages was recently shown to correspond to
up-regulation of FLIP, in association with a decrease in Fas-mediated
apoptosis (47). Thus, the remaining maturing macrophages
may be protected from Fas-dependent apoptosis due to expression of
FLIP. The last question is whether this in vitro phenomenon has any
relevance to in vivo situations. Phagocytosis was suggested to be
defective in lupus patients due to rare genetic defects such as
complement deficiencies (48) or specific alleles such as
Fc
RIIIa (49). Studies of handling of
immune complexes showed that both FcR and complement
receptors are saturable (50, 51, 52, 53). Taken together, it is
suggested that what is demonstrated in rare individuals with genetic
deficiencies that develop SLE or SLE-like disease may be found in the
larger population of SLE patients as a common endpoint pattern of
altered phagocytosis. In the example of this study, accelerated
apoptosis characterized most patients and was the main cause of reduced
in vitro interaction with apoptotic cells. The relevance to the in vivo
state is not known, but several findings may support altered
phagocytosis of apoptotic cells in SLE. First, in this study, both
freshly isolated and maturing monocytes showed accelerated apoptosis
with a reduced capacity of the remaining mature macrophages to clear
apoptotic cells. Second, increased levels of nucleosomes were found in
plasma of patients with SLE (54). Nucleosomes are formed
in the process of programmed cell death, but in efficient phagocytosis,
nucleosomes are generally created within a phagocyte following
ingestion of cells undergoing early apoptosis (55). In
this way, nucleosomes are not released to the plasma, where another
safety mechanism in the form of nucleases exists. The pathogenicity of
nucleosomes was demonstrated both by the finding that nucleosomes are
the preferred targets of anti-DNA autoantibodies (56)
and by their ability to induce immunoproliferative response
(57) and IL-6 activity (58). Recently, it was
shown that SLE-like disease develops in mice deficient in DNase I,
which is the major nuclease present in the serum (59).
Third, in animal models, mice deficient in C1q (60), C4
(61), ABC1 cassette transporter (62), and mer
(19) are deficient in receptors or factors required for
interaction with apoptotic cells, and in their absence develop
autoimmunity or lupus-like disease. Fourth, in lupus patients, serum
factors may have additional inhibitory (38, 39, 63) or
proinflammatory (64) effects. In summary, iC3b-opsonized
apoptotic cell interaction with macrophages is altered, in vitro, in a
significant number of SLE patients. It may be related to several
genetical, environmental, or disease-driven factors, but in this study
it was associated with accelerated apoptosis of monocytes/macrophages.
Altered interaction with apoptotic cells could contribute to induction
or persistence of systemic autoimmunity. However, at present, the in
vivo biological significance of in vitro data remains to be
determined.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Dror Mevorach, Laboratory for Cellular and Molecular Immunology, Department of Medicine, Hadassah University Hospital, P.O. Box 12000, Jerusalem 91120, Israel. E-mail address: mevdm{at}netvision.net.il
3 Abbreviations used in this paper: SLE, systemic lupus erythematosus; CHO, Chinese hamster ovary; FLIP, Fas-associated death domain-like IL-1-converting enzyme-inhibitory protein; PI, propidium iodide; RA, rheumatoid arthritis.
Received for publication May 29, 2001. Accepted for publication September 12, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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v5 and CD36, and cross-present antigens to cytotoxic T lymphocytes. J. Exp. Med. 188:1359.1 integrin-dependent mechanism of leukocyte adherence to apoptotic cells. J. Immunol. 162:4842., PGE2, and PAF. J. Clin. Invest. 101:890.[Medline]
RIIIa (CD16) alters receptor function and predisposes to autoimmune disease. J. Clin. Invest. 100:1059.[Medline]
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