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*
Division of Pulmonary and Critical Care Medicine and
The Heart and Lung Institute, Ohio State University College of Medicine and Public Health, Columbus, OH 43210; and
Progenitor, Inc., Columbus, OH 43210
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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R cross-linking. Monocytes cultured on immobilized IgG,
which induces FcR cross-linking, were protected from apoptosis,
whereas monocytes cultured with equivalent concentrations of
F(ab')2 IgG or 50 times higher concentrations of soluble
IgG, neither of which induces FcR cross-linking, were not protected.
Moreover, this protection was transferable, as supernatants from
immobilized IgG-stimulated monocytes protected freshly isolated
monocytes from apoptosis and contained functional M-CSF, a known
monocyte survival factor. M-CSF mediated the monocyte survival induced
by FcR cross-linking, as neutralizing anti-human M-CSF Abs
blocked the monocyte protection provided by either immobilized IgG or
IgG-stimulated monocyte supernatants. These findings demonstrate a
novel mechanism by which deposited IgG targets tissue macrophage
accumulation through FcR-mediated M-CSF release. This pathway may
play an important role in promoting and potentiating IgG-mediated
tissue injury. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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R cross-linking on immobilized human IgG,
mimicking the effects of immune complexes or deposited IgG on these
cells, induces monocytes to release biologically active IL-8 and
monocyte chemoattractant protein-1
(MCP-1)3 (15, 16, 17). These
chemokines mediate the regulated recruitment of neutrophils and
monocytes in the response to opsonized bacteria and the unregulated
influx of these inflammatory leukocytes in immune complex-associated
diseases. Localized MCP-1 recruits monocytes to tissues targeted by IgG deposition (15). Regulated monocyte recruitment and survival in response to IgG-opsonized bacteria may be beneficial in resolving localized bacterial infection (18), but unregulated recruitment and survival of monocytes in immune complex-related diseases may lead to tissue injury (1, 10, 19, 20). However, MCP-1 does not promote monocyte survival (21), suggesting that additional monocyte survival factors must be present. Thus, the goal of this study was to characterize the mechanisms that relate IgG deposition to macrophage accumulation to provide new targets to reverse tissue injury in Ab-mediated diseases.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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RPMI 1640 was obtained from BioWhittaker (Walkersville, MD). FCS was obtained from HyClone (Logan, UT). Polymyxin B was obtained from Rohrer Pharmaceuticals (New York, NY). Pooled human IgG (Sandoglobulin) was purchased from Sandoz (Basel, Switzerland). Human serum albumin was obtained from Sigma (St. Louis, MO). Immulon IV tissue culture plates were obtained from Dynatech (Chantilly, VA). Recombinant human M-CSF, murine anti-M-CSF mAbs (IgG2a isotype), and M-CSF ELISAs were obtained from R&D Systems (Minneapolis, MN). F(ab')2 of IgG (Fc domains removed by the manufacturer) and monoclonal IgG2a isotype Abs were obtained from The Jackson Laboratory (Bar Harbor, ME). Papain used to generate Fab of IgG Abs was obtained from Pierce (Rockford, IL). Wizard Miniprep DNA binding columns were obtained from Promega (Madison, WI). Charged membranes used to transfer DNA and the ECL detection system were obtained from Amersham (Hybond, Aylesbury, U.K.). Nick labeling of small m.w. DNA was modulated by Nick Translation Systems (Life Technologies, Gaithersburg, MD). TdT immunoassay kits were obtained from Oncogene Research Products (Cambridge, MA). Slides for immunohistochemical studies were obtained from Lab-Tek (Arlington Heights, IL).
Cellular preparation and cell culture
Monocytes (66 ± 2.1% CD14+) were isolated from the heparinized blood of normal human volunteers as previously described (16) and resuspended at 2 x 106 monocytes/condition in RPMI 1640, 5% inactivated FCS, and polymyxin B (10 µg/ml). The presence of polymyxin B did not alter the ability of unstimulated cells to undergo apoptosis. Using light microscopy and Diff-Quick (Dade Diagnostics, Aquada, Puerto Rico) staining, there were an average of 65% monocytes, 34% lymphocytes, and <1% neutrophils in the preparations.
The monocytes were enriched by first diluting whole blood 1/1 with PBS and layering the blood/saline mixture onto 20 ml of Histopaque. The mixture was centrifuged at 2000 rpm at 18°C for 20 min without braking. The mononuclear layer was pooled and washed once with RPMI at 14,000 rpm for 10 min at 4°C with the brake on and an additional two times at 1,050 rpm. The cells were counted on a hemocytometer, resuspended to 5 x 107 cells/ml with RPMI containing 10% FBS in a polypropylene tube, and rotated for 1 h at 4°C. The cells were layered onto cold FBS at a 1/1 ratio for 20 min to allow the monocytes to fall to the bottom of the tube. The monocytes were collected, washed twice with RPMI at 4°C for 10 min, and recounted. The monocytes were suspended in RPMI/5% FBS (2 x 106 cells/condition) for these studies. These monocytes were cultured with endotoxin-free pooled human IgG that had been either 1) immobilized to tissue culture plates overnight followed by washing of the plates twice with sterile PBS/polymyxin B the following day, or 2) added solubly to monocyte preparations for 24 h at 37°C in 5% CO2. Additionally, serial concentrations of recombinant human M-CSF (0.01–100 ng/ml) were added to monocytes (106/ml) and incubated for 24 h at 37°C in 5% CO2. The IgG (25 µg/0.25-mm2 well) was immobilized by random binding overnight at 4°C, and nonadherent IgG was washed off the following day. By PAGE with Western blotting, the maximum of approximately 0.5 µg/well of IgG bound. Apoptotic changes were quantitatively measured using densitometry of cytosolic oligonucleosomal DNA fragments.
After monocytes had been enriched from PBMC, lymphocyte subsets were further enriched by incubating them on nylon wool columns at 37°C for 45 min and eluting nonadherent cells from the columns using RPMI 1640 medium as previously described (15). The lymphocytes were 98.5 ± 1.5% CD14-, 86 ± 4% CD3+, 13 ± 3% CD56+, and 0.5 ± 0.7% CD56+/CD3+. After purification, the lymphocytes were washed, counted, and resuspended at 107/ml in 5% FCS, RPMI, and polymyxin B. Subsequently, the lymphocytes were cultured on either immobilized IgG (0.5 µg/well) or adherence to plastic plates for an additional 24 h. The cells were then recovered and assayed for apoptosis by evaluating the cytosolic DNA fragmentation content as described above.
In other experiments, monocytes (2 x 106/condition) were incubated on equivalent concentrations of immobilized 1) pooled human IgG, 2) F(ab')2 of IgG, 3) human serum albumin, or 4) without plated protein for 24 h at 37°C in 5% CO2. Additionally, to evaluate the role of M-CSF in the monocyte protection afforded by immobilized IgG, monocytes were incubated on plates that had been coated with immobilized IgG (0.5 µg/well) alone or in the presence of Fab of a specific neutralizing anti-human monoclonal M-CSF Ab (1 µg/ml) or of Fab preparations of an isotype IgG2a isotype control Ab (1 µg/ml) or on plastic without IgG for 24 h at 37°C in 5% CO2. Apoptotic changes were assayed using both cytosolic DNA assessments as well as the TdT immunohistochemical assay. Fab Abs were prepared using papain cleavage, and effective cleavage was ascertained by demonstrating change in m.w. of the Ab using immunoblotting with an anti-murine IgG Ab. Lastly, to discern whether the released form of M-CSF could also protect freshly isolated monocytes from apoptotic changes in a paracrine manner, cell-free supernatants from monocytes that were incubated on immobilized IgG (0.5 µg/well) were added to freshly isolated monocytes (2 x 106 monocytes/condition) at a 1/5 concentration alone or after immunodepletion of M-CSF using an anti-M-CSF IgG or control IgG (1 µg/ml) and were incubated for an additional 24 h at 37°C in 5% CO2.
Determination of immobilized vs soluble IgG concentrations
To quantify IgG that bound to the plates, immobilized IgG (loading concentration, 1 or 100 µg/ml) was removed in Laemmli sample buffer and resuspended in the initial volume at which it was plated (0.2 ml). Bound IgG concentrations were determined by PAGE (0.02 ml/lane) and immune blotting with an anti-human IgG Ab (R&D Systems). Bound IgG concentrations were compared with soluble IgG concentrations by comparing serial 2-fold dilutions of IgG isolated from culture plates to serial 2-fold concentrations of soluble IgG (starting at 2 µg/lane). When these bands were densitometrically analyzed and plotted, IgG plated at 100 µg/ml was found to coat about 0.5 µg/0.25 ml well or 2 µg/ml.
To quantify monocyte adherence to IgG, human serum albumin, F(ab')2, and plastic, total numbers of plated cells were counted after 24-h incubations by counting three random high powered fields. The nonadherent cells were recovered, and the numbers of adherent cells were determined for each condition by counting three random, blinded, high power fields.
Apoptosis assays
Cytosolic DNA fragmentation assay. After 24-h incubations, monocytes (1 x 106/ml) were collected and lysed in Triton-X lysis buffer (1% Triton-X 100, 50 mM Tris-HCl (pH 7.9), 10 mM EDTA, and 50 µg/ml RNase A) for 10 min, and the cytosolic fraction of the cell was recovered. To exclude intact chromosomal DNA, samples were purified using Wizard Miniprep DNA binding columns, which removes DNA fragments greater than 20K bp, and recovered cytosolic DNA fragments were separated by a 1.8% agarose gel. The DNA was stained using SYBER-green staining of the gels and analyzing the bands on a digital gel documentation system (GelDoc 1000, Bio-Rad, Hercules, CA).
In Fig. 5
, the DNA gel was developed using peroxidase-labeled
single-stranded DNA that by Southern blotting thus appears to be a
negative of the other gels.
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M-CSF antigenic quantification
After 24 h, cell-free supernatants from monocytes that had been incubated on immobilized or soluble IgG were recovered, and M-CSF was assayed using a commercially available ELISA. Samples were measured in duplicate at four dilutions.
M-CSF biologic function assay
To determine whether the antigenic M-CSF was also biologically active, a methylcellulose CFU assay was performed. This assay measured monocyte-inducing activity from blasts using freshly isolated human bone marrow (through Division of Bone Marrow Transplantation, Ohio State University). To determine CFU activity, supernatants from monocytes incubated on 1) immobilized IgG, 2) F(ab')2 IgG, or 3) plastic alone were incubated with bone marrow. These supernatants were compared with supernatant from monocytes incubated with F(ab')2 IgG. To determine whether M-CSF in the conditioned supernatants modulated monocyte CFU activity, a monoclonal anti-human M-CSF Ab (R&D Systems) or an isotype IgG2a control were used (both at 1 µg/ml) to block the effect.
Statistical analysis
For ELISA measurements and M-CSF biological assays, ANOVA with post-hoc testing was performed using MINITAB software (State College, PA). To quantitate apoptosis, DNA fragments were assessed by densitometry, and statistical comparisons were performed between experimental conditions using ANOVA with post-hoc testing. Similarly, quantification of annexin V staining of apoptotic cells was evaluated by flow cytometry, and statistical analysis was determined by ANOVA with post-hoc testing. All results are reported as the mean ± SEM, and statistical significance was defined as p < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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R
cross-linking
To determine whether FcR cross-linking induced by immobilized
IgG prevents monocyte apoptosis, we plated equivalent concentrations of
monocytes on immobilized IgG or equivalent concentrations of
F(ab')2 fragments on IgG, human serum albumin, or plastic.
After 24-h incubations, monocytes incubated on immobilized IgG were
morphologically different from those incubated on equivalent
concentrations of immobilized F(ab')2 of IgG, human serum
albumin, or plastic plates as assessed by light microscopy (Fig. 1A). Moreover, there was no
difference in the total numbers of cells present in the different
experimental conditions (IgG, 296 ± 13 cells/high powered field;
F(ab')2, 287 ± 20 cells/high powered field; human
serum albumin, 296 ± 19 cells/high powered field; plastic,
260 ± 18 cells/high powered field; p = 0.52).
However, IgG stimulated monocyte adherence significantly better than
the other conditions (p < 0.0001 vs all other
conditions; Fig. 1B). The immobilized IgG-treated monocytes
were protected from apoptosis as measured by the lack of cytosolic DNA
fragmentation (p < 0.01 vs other conditions;
Fig. 2) and the lack of TdT staining
(Fig. 9). In contrast, cells incubated on immobilized
F(ab')2 of IgG or on uncoated plastic culture plates, which
do not induce FcR cross-linking, underwent apoptosis as demonstrated
by cytosolic DNA oligonucleosomal fragmentation (Fig. 2). Immobilized
IgG protected monocytes from apoptosis in a dose-dependent manner (Fig. 3). By densitometry, only the 100 µg/ml
plating dose of IgG suppressed oligonucleosomal DNA fragmentation
statistically more than that in unstimulated cells (control;
p = 0.025). To exclude the possibility that small
numbers of lymphocytes contaminating enriched monocyte preparations
were responsible for the DNA fragmentation, purified lymphocyte
preparations demonstrated only minimal evidence of DNA fragmentation at
24 h regardless of incubation on IgG or plastic alone
(p = 0.68; Fig. 4).
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Immobilizing IgG to culture plates reduced IgG concentrations
50-fold (from 100 to 2 µg/ml; Fig. 5
A). Despite the clear
reduction in IgG concentration after immobilization, only immobilized
IgG protected monocytes from apoptosis, assayed by the lack of
oligonucleosomal DNA fragmentation (Fig. 5B).
IgG stimulation induces biologically active M-CSF release from monocytes
Immobilized IgG induced the release of 7.3 ± 1.6 ng/ml of
M-CSF (Fig. 6A). In contrast,
immobilized F(ab')2 of IgG, immobilized human serum
albumin, or plastic plates, which do not stimulate FcR
cross-linking, induced <0.03, 0.4 ± 0.3, or 0.2 ± 0.2
ng/ml, respectively (p < 0.0001 compared with
immobilized IgG; Fig. 6A). Moreover, deposited IgG was
approximately 10,000-fold more potent than soluble IgG in inducing
M-CSF (Fig. 6B). FcR-mediated M-CSF was biologically
active, as evidenced by the ability to induce CFU activity in cells
from human bone marrow. This effect was inhibited by a neutralizing
monoclonal anti-human M-CSF Ab, but was not inhibited by an isotype
control Ab (Fig. 6C). Importantly, in the absence of IgG,
recombinant human M-CSF was able to protect monocytes from cytosolic
DNA fragmentation in a dose-dependent manner (Fig. 7). M-CSF concentrations of 1 and 10
ng/ml induced monocyte survival more than unstimulated cells
(p < 0.05; Fig. 7).
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R-stimulated monocyte survival is mediated by M-CSF
To determine whether M-CSF was the mediator of the FcR-mediated
survival, monocytes were incubated on 1) immobilized IgG alone, 2)
immobilized IgG with Fab of a neutralizing anti-human M-CSF Ab, 3)
immobilized IgG with Fab fragments of an isotype control Ab, or 4)
plastic culture plates alone. Only the neutralizing anti-human
M-CSF Ab reversed the protection against monocyte apoptosis afforded by
the immobilized IgG as gauged by densitometry of cytosolic DNA
fragments (p < 0.025 for IgG and IgG plus
isotype control vs unstimulated cells (control) or IgG plus 
M-CSF;
Fig. 8) and TdT immunohistochemical
analysis (Fig. 9).
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; p < 0.05 for IgG
and IgG plus isotype IgG vs unstimulated cells (control) or IgG plus
M-CSF).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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R-mediated activation and M-CSF release. Deposited
IgG protects monocytes by inducing M-CSF in both an autocrine and a
paracrine manner, which may amplify monocyte survival at the site of
immobilized IgG. M-CSF induction and monocyte survival are specifically
mediated by IgG-induced FcR cross-linking, as deposited IgG promotes
monocyte survival while 50-fold higher concentrations of soluble IgG or
equivalent concentrations of immobilized F(ab')2 of IgG,
which do not induce monocyte FcR cross-linking, do not. Moreover,
immobilized IgG is at least 10,000-fold more potent at inducing M-CSF
release by monocytes than soluble IgG. The released M-CSF is
biologically active as measured by monocyte CFU activity. As evidence
of M-CSF’s role in the IgG-induced monocyte survival, neutralizing
anti-M-CSF IgG, but not isotype control IgG, reverse the autocrine
protection induced by deposited IgG. Furthermore, in the absence of
IgG, recombinant human M-CSF prevents the monocyte apoptosis. M-CSF
released by the monocytes also acts in a paracrine manner, as cell-free
supernatants from monocytes incubated on immobilized IgG transfer
protection to freshly isolated monocytes. Moreover, this protection can
be removed with anti-M-CSF, but not isotype control, Abs.
The novel finding that deposits of IgG induce monocyte FcR
cross-linking to protect monocytes from apoptosis has relevance to
human disease. This relevance is underscored by finding that tissue
compartments injured in response to IgG deposition, like joints in
rheumatoid arthritis or lungs in pulmonary fibrosis, have expanded
numbers of macrophages (4, 7, 8, 10). We have previously demonstrated
that monocyte FcR cross-linking induces monocytes to produce MCP-1
production (15), a powerful monocyte chemoattractant. In host defense,
regulated monocyte recruitment and MCP-1 production are critical to
clearing opsonized bacteria from target organs and promoting host
survival in compartmentalized infection (18). However, MCP-1 does not
protect monocytes from apoptosis; thus, newly recruited monocytes could
not survive under the influence of MCP-1 alone (21). In contrast to the
benefit of macrophage targeting in infectious diseases, unregulated
macrophage-directed chemokine production and macrophage
accumulation are hallmarks of joint injury in rheumatoid arthritis (2, 7, 13), renal injury in glomerulonephritis (1, 3, 14), and lung injury
in pulmonary fibrosis (4, 10, 11, 12). Thus, the factors that affect
monocyte recruitment and survival are important to host homeostasis.
Since MCP-1 does not protect newly recruited monocytes from apoptosis
(21), we hypothesized that a separate FcR-mediated pathway was
responsible for directing newly recruited monocytes to become
macrophages.
We found that FcR-stimulated M-CSF release controlled monocyte
survival. These observations have in vivo relevance, as homozygous
M-CSF-deficient osteopetrosis
(op-/op-) mice are
deficient in absolute numbers of circulating monocytes and tissue
macrophages, including a deficiency in the number of osteoclasts
resulting in dysfunctional bone remodeling (23, 24). M-CSF is
responsible for this absolute macrophage and osteoclast deficiency, as
injections of recombinant M-CSF reverse the problem (25, 26, 27). Studies
involving op-/op- mice
demonstrate that M-CSF and macrophages are important determinants of
IgG-associated human diseases, including models of rheumatoid arthritis
and glomerulonephritis (3, 20, 28, 29, 30). Similarly, FcR-deficient
mice are protected from targeted organ injury induced by localized
deposits of IgG (29), suggesting a critical role for FcR in immune
complex-mediated inflammation. We bridge these independent observations
by finding that monocyte FcR cross-linking by deposited IgG induces
biologically active M-CSF production. We speculate that once monocytes
are recruited to the tissue compartment via FcR-stimulated MCP-1
production (15), FcR-stimulated M-CSF release induces their
survival. This pathway focuses on a new target to reduce targeted
tissue inflammation in human immune complex-mediated diseases and
supports the concept that M-CSF is a critical monocyte survival factor
that allows macrophage accumulation (31). This concept is supported by
the observation that enforced expression of the antiapoptotic protein
Bcl-2 in monocytes of
op-/op- animals
corrects much of the underlying bone problems and macrophage
deficiency, suggesting that accelerated apoptosis of monocyte
precursors is a fundamental problem in this M-CSF-deficient animal
(31).
Of interest, other CSFs, including GM-CSF and G-CSF, are powerful
survival factors for neutrophils (32, 33). However, GM-CSF does not
augment monocyte survival in the
op-/op- mouse (34),
suggesting that the specificity of these growth factors does not
include monocyte survival. While other authors have shown that M-CSF
augments monocyte survival (35), the seminal observations in this paper
are that monocyte FcR cross-linking protects monocytes from
apoptosis and that this protection is mediated through the production
and release of M-CSF.
Previous investigators determined that inflammatory cytokines,
including IL-1ß, TNF-, IFN-, and GM-CSF, can promote monocyte
survival (21). In addition, LPS can induce monocyte survival (36).
Although these studies added important insights into the regulation of
monocyte survival, they did not address the role of deposited IgG as a
potential mediator of monocyte survival. This paper extends their
findings to make the observation that deposits of IgG can also promote
monocyte survival through the production of M-CSF.
In summary, we show that immobilized IgG protects monocytes from
apoptosis through FcR cross-linking, as assayed by cell morphology,
cytosolic DNA fragmentation, annexin V staining, and TdT
immunohistochemical analysis. The ability of IgG to mediate monocyte
protection appears dependent on cross-linking monocyte FcR. This
property is illustrated by the finding that immobilized IgG prevents
monocyte apoptosis, while soluble IgG or F(ab')2 IgG, do
not. Moreover, immobilized IgG is 10,000-fold more potent in
stimulating monocyte M-CSF release than is soluble IgG. Interestingly,
apoptosis prevention conferred by monocyte FcR cross-linking is
mediated through the production and secretion of FcR-mediated M-CSF,
suggesting that immobilized IgG may regulate monocyte survival through
both autocrine and paracrine effects. These novel observations provide
a potential mechanism to explain targeted organ injury caused by
macrophages in immune complex diseases.
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Acknowledgments |
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receptor studies. |
Footnotes |
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2 Address correspondence and reprint requests to Dr. Clay B. Marsh, Division of Pulmonary and Critical Care Medicine, N-325 Means Hall, 1654 Upham Dr., Ohio State University Medical Center, Columbus, OH 43210. E-mail address:
3 Abbreviation used in this paper: MCP-1, monocyte chemoattractant protein-1.
Received for publication November 24, 1998. Accepted for publication February 19, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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receptor cross-linking induces peripheral blood mononuclear cell monocyte chemoattractant protein-1 expression: role of lymphocyte FcRIII. J. Immunol. 158:1078.[Abstract]
receptor cross-linking induces IL-8 production. J. Immunol. 155:3161.[Abstract]
R-mediated pathways. J. Immunol. 157:2632.[Abstract]
, and IL-1ß prevent programmed cell death (apoptosis) in human peripheral blood monocytes. J. Immunol. 146:1541.[Abstract]
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