(Circulation. 1999;99:1740-1746.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Intraperitoneal Administration of Anti–c-fms Monoclonal Antibody Prevents Initial Events of Atherogenesis but Does Not Reduce the Size of Advanced Lesions in Apolipoprotein E–Deficient Mice
Presented in part at the 69th Scientific Sessions of the American Heart Association, New Orleans, La, November 10 to 13, 1996, and published in abstract form in Circulation (1996; 94[suppl I]:I-633).
From the Departments of Geriatric Medicine (T.M., M.Y., H.K., T.I., H.Y., H.S., T.K.) and Molecular Genetics (H.K., S.N., S.-I.N.), Graduate School of Medicine, Kyoto University, Japan.
Correspondence to Masayuki Yokode, MD, Department of Geriatric Medicine, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan. E-mail yokode{at}kuhp.kyoto-u.ac.jp
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Abstract |
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Background—Atherosclerosis results from complex inflammatory-fibroproliferative responses. To elucidate the central role of macrophage and macrophage-colony stimulating factor (M-CSF) during atherogenesis, we used a new strategy to administer to adult apolipoprotein E (apoE)-deficient mice a monoclonal antibody (AFS98) raised against c-fms, the receptor of M-CSF.
Methods and Results—When 6-week-old apoE-deficient mice were fed a high-fat diet and injected with 2 mg of AFS98 intraperitoneally on alternate days for 6 weeks, accumulation of macrophage-derived foam cells in the aortic root was suppressed by 70% compared with that in controls. This preventive effect was associated with neither remarkable decrease of the number of circulating monocytes nor systemic growth retardation. In contrast, when apoE-deficient mice that had been fed a high-fat diet from 6 weeks of age were given AFS98 from 12 to 18 weeks of age, a minimal protective effect on lesion size was observed.
Conclusions—These results suggest that (1) macrophage and M-CSF/c-fms play an essential role in the arterial wall during development of the fatty streak lesion and (2) blockade of the M-CSF/c-fms pathway could act as protection from at least early atherogenesis but could have a less preventive effect on maintenance of the advanced lesions.
Key Words: antibodies • atherosclerosis • leukocytes
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Introduction |
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Atherosclerosis results from complex inflammatory-fibroproliferative responses.1 It is widely accepted that the earliest event of atherogenesis is the adhesion of circulating leukocytes on the surface of vascular endothelial cells and migration into the subendothelial space. Recent investigations suggested that monocyte/macrophage might play the central role in the vast range of atherogenesis, that is, from fatty streak formation to plaque rupture.2 3 4 Apolipoprotein E (apoE)-deficient mice develop hypercholesterolemia and premature atherosclerotic lesions even on a low-fat diet and are used widely for studying atherogenesis.5 6 7 8 9 10
Macrophage colony-stimulating factor (M-CSF) and its receptor, c-fms, have been known to play key roles in differentiation and proliferation of the monocyte/macrophage cell lineage.11 12 Macrophages and macrophage-derived foam cells resident within atheroma have been shown to express M-CSF mRNA and secrete active M-CSF.13 14 It has also been reported that c-fms is expressed in atheromatous lesions.15 16 Although these results indicate that M-CSF could be at least associated with atheroma formation, it is yet to be clarified how M-CSF functions in the arterial wall with regard to the development of atherosclerosis. Yoshida et al17 reported that op/op mice homozygous for a recessive osteopetrosis mutation have a genetic defect for M-CSF production, and this observation was confirmed by the report of Naito et al18 that differentiation of the monocyte/macrophage cell lineage was disrupted in these mice. Smith et al19 and Quiao et al20 crossed apoE-deficient mice with op/op mice and found that atherogenesis was delayed in these "double knockout mice." However, because systemic monocyte counts are decreased markedly in the op/op mice, owing to hematopoietic suppression,21 it remains unanswered whether the slowed atherogenesis in the "double knockout mice" was due to a functional blockade of M-CSF locally in the vessel wall during development of atheroma or merely a consequence of reduced systemic monocyte numbers. Complicating matters further, it has been shown that large doses of M-CSF could reduce the severity of atheromatous lesions in rabbits.22
In this study, we addressed the following questions: (1) Could the M-CSF/c-fms signaling pathway have any functional role in the vessel wall during atherogenesis? (2) If so, how and when does it act in the vast stage of atherogenesis? To answer these questions, we invented a new strategy for postnatal blockade of the M-CSF/c-fms signaling pathway in initial or advanced atherosclerotic lesions of adult apoE-deficient mice by administering a monoclonal antibody (mAb) raised against c-fms. We report here that the endogenous M-CSF/c-fms signaling pathway plays a promotive role at least in the initial stage of atherogenesis and that blockade of this pathway can prevent development of the early atherosclerotic lesions.
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Methods |
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Mice
The apoE-deficient mice (hybrid 129ola x C57BL/6) were the generous gift of Dr Edward M. Rubin (University of California at Berkeley).5 7 Mice were kept in a temperature-controlled facility on a 14-hour light/10-hour dark cycle with free access to food and water. After being weaned at 4 weeks of age, mice were fed a normal diet (CMF, containing 8.7% (wt/wt) fat and 0.063% (wt/wt) cholesterol; Oriental Yeast) for 2 weeks. At 6 weeks of age, they were fed a high-fat diet containing 20% fat (wt/wt) and 0.3% cholesterol (wt/wt) (Oriental Yeast).
Antibody Administration
AFS98, a rat monoclonal anti-murine c-fms antibody
(IgG2a), which inhibits M-CSF–dependent colony formation and cell
growth by blocking the binding of M-CSF to its receptor, has been
described previously.23 Two milligrams of AFS98
(purified by 50% ammonium sulfate precipitation) in 200 µL of PBS
was administered intraperitoneally to each mouse
for 6 weeks on alternate days. Four female mice were used in each
experiment. For control, PBS or 2 mg of an isotype-matched irrelevant
rat IgG that does not recognize mouse macrophages was used.
Experimental Protocols
Our experimental protocols are illustrated in Figure 2
. In protocol A, 2 mg of AFS98,
irrelevant IgG, or 200 µL of PBS was administered to each mouse fed a
high-fat diet from 6 to 12 weeks of age. In protocol B, 6-week-old mice
were fed a high-fat diet for 12 weeks. After the mice reached 12 weeks
of age, they were given 2 mg of AFS98 or PBS for 6 weeks. After each
experimental period, mice were killed by cervical dislocation and used
for further analysis. All experimental protocols were performed
in accordance with the guidelines of Kyoto University.
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Tissue Preparation
After the mice were killed, the freshly removed hearts were
snap-frozen in OCT embedding medium (Miles) and sequentially cut into a
total of 60 (6-µm-thick) sections around the aortic sinus as reported
previously.24 Out of 60 sections, every third slice (a
total of 20) was stained with oil red O (Sigma Chemical) and Meyer's
hematoxylin solution (Wako Pure Chemical Industries). The rest of the
sections were used for immunohistochemistry. The rat mAb BM8 labeled
with biotin (BMA Biochemicals AG) or biotinylated rabbit antiserum
BA-4001 (mouse adsorbed, Vector Labs) was used as a specific marker for
mouse macrophages or rat IgG, respectively. For
macrophage staining, we used the Tyramide Signal Amplification
system (NEN Life Science Products) to amplify the weak signal.
Endogenous peroxidase activity was blocked by incubating
each section in 3% (vol/vol)
H2O2 in methanol. An
avidin-biotin blocking kit (Vector Labs) was used. BM8 and BA-4001 were
used at a dilution of 1:1000 and 1:200, respectively. After horseradish
peroxidase–conjugated streptavidin (Vector Labs) was added to the
section, antibody binding was visualized with diaminobenzidine (Vector
Labs). For smooth muscle cell staining, we used mouse monoclonal
anti-human smooth muscle actin antibody 1A4 labeled with horseradish
peroxidase (DAKO). Each section was counterstained with Meyer's
hematoxylin solution.
Image Analysis
Each aortic sinus section was evaluated for oil red O staining
by capturing images directly from an RGB camera attached to a light
microscope (Axioscope, Karl Zeiss) and displayed on a Trinitron RGB
monitor. Image analysis was conducted with the use of KS400
software (Karl Zeiss Vision). For each animal, 20 sequential sections
as described in "Tissue Preparation" were examined, and the sum of
the lesion area was calculated and expressed in square
micrometers.
Flow Cytometric Analysis
Mouse peritoneal cells were suspended in Hanks' solution
(Nissui) containing 1% BSA. After incubation with mouse serum, AFS98
or control rat IgG2a was added at the concentration of 1 µg/mL. After
15 minutes of incubation, cells were washed twice by the Hanks'/BSA
solution. FITC-mouse anti-rat 
-chain mAb was added. Cells were gated
to exclude unusual background interference, and the population
containing peritoneal macrophages was analyzed by XL
(Coulter).
Statistical Analysis
Data are expressed as mean±SD. The lesion area, serum total
cholesterol, and hematologic parameters of mice
were compared by ANOVA with the use of Abacus Statview software
(version 4.5). A value of P<0.05 was considered
statistically significant.
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Results |
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Administration of AFS98 Prevented Development of Fatty Streaks in ApoE-Deficient Mice
We first conducted flow cytometric analysis to confirm that AFS98 could recognize c-fms on the peritoneal macrophages from apoE-deficient mice (Figure 1
). To
study animals with early and advanced lesions of atheroma,
we designed protocols A and B (Figure 2
).
As demonstrated in Figure 3a, the mice
that had been injected with PBS showed typical fatty streak lesions in
the aortic root stained by oil red O. The majority of the cellular
component of this lesion was immunolabeled with the rat mAb BM8 against
murine macrophage (Figure 3b), demonstrating that these
foam cells were derived from monocyte/macrophages. In striking
contrast to the PBS control animals, the aortic lesion size in the mice
given AFS98 was remarkably smaller (Figure 3, a and c). As shown
in Figure 3d, very few cells were immunostained by
BM8 in the aorta of the mice given AFS98, showing that the mice
injected with AFS98 had a remarkably lower number of
macrophages in the arterial wall. When the areas of
the aortic lesions were analyzed quantitatively, the total
aortic lesion area of mice injected with AFS98 was 2390±204
µm2, which was 
30% of that in the PBS
control mice (P=0.024) (Figure 4). To confirm that the preventive effect
of AFS98 was caused by selective blockade of the M-CSF/c-fms
signal transduction pathway, another experiment was performed. In this
experiment, apoE-deficient mice were fed a high-fat diet and were
injected with PBS or the isotype-matched rat irrelevant IgG during the
same period. As shown in Figure 5, a and
b, injection of the irrelevant IgG had no such preventive effect on
atherogenesis as seen with AFS98 injection. When the lesion size was
examined by quantitative analyses, no significant difference
was found between the animals injected with the irrelevant IgG and PBS
(data not shown).
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Prevention of Atherogenesis by AFS98 Was Not Associated With
Remarkable Changes in Monocyte Differential Count and Body
Weight
Because the observations above suggested that the
M-CSF/c-fms signal transduction pathway plays a significant
role in the accumulation of monocyte-derived macrophages in the
initial atheromatous lesion, we asked whether the
preventive effect of AFS98 could be due to the depletion of monocytes
from the circulation. In contrast to the observation in "double
knockout" apoE-deficient op mice,19
AFS98 administration failed to result in a statistically significant
reduction of the peripheral blood monocyte count in our
study (Table). Furthermore, the
mice given AFS98 appeared to be healthy, and their body weight did not
differ significantly from that of the control mice during the whole
course of the experiments (data not shown). There was no significant
difference in serum total cholesterol level between mice
given AFS98 and those given irrelevant IgG (981±368, 855±98 mg/dL,
respectively). These results suggest that although AFS98 caused drastic
prevention of macrophage accumulation in the aortic wall, this
effect was not attributed to suppression of differentiation of the
monocyte lineage in the hematopoietic tissues.
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AFS98 Administration Did Not Reduce Size of Advanced
Atherosclerotic Lesions
Because AFS98 protected fatty streak formation, we next tested
whether the antibody could have a similar preventive effect on the more
advanced lesions. For this purpose, we conducted protocol B by
preparing 12-week-old mice that had been fed a high-fat diet (Figure 2). From the results of protocol A (Figure 3, a and b),
it was deducible that these mice would have aortic lesions filled with
a large number of macrophages. To these animals, we
administered either AFS98 or PBS intraperitoneally
for 6 more weeks and then examined the aortic lesions. In
contrast to the results of protocol A, AFS98 had very little effect on
the size of aortic lesions in these older animals. As demonstrated in
Figure 6, a and b, the aortic lesion
stained by oil red O did not differ in size significantly between
AFS98-injected mice and PBS-injected mice. The total aortic lesion area
of mice injected with AFS98 and PBS was 30 728±2248 and
31 753±17 483 µm2, respectively. To
exclude the possibility that the antibody could not be delivered to the
atheromatous lesions, we stained sections with anti-rat
IgG antiserum. As shown in Figure 6g, we could detect the
antibody in the lesion of mice given AFS98 in contrast to the mice
given PBS (Figure 6h). We further studied whether AFS98 affected
the cell numbers of macrophage or vascular smooth muscle cells,
the 2 major cellular components in the atheromatous
lesion, by using selective antibodies against these cells. As shown in
Figure 6, c through f, AFS98 did not reduce the staining of
macrophages, nor did it change the staining pattern of vascular
smooth muscle cells.
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Discussion |
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Thus far, a variety of experimental animal models including rabbit, nonhuman primate, pigeon, and pig have been used to study atherogenesis. Recently, apoE-deficient mice created by genetic engineering enabled us to investigate further the molecular basis for atherosclerosis formation. To determine the crucial cellular and molecular components of atherogenesis, many experiments with these mice were conducted by crossing them with other mice carrying various genetic defects or activated transgenes.19 20 25 26 27 28 29 30 31 Among the various genes proposed to be involved in atherogenesis, M-CSF and its receptor c-fms are known to regulate several monocyte functions including differentiation in the bone marrow, growth in the peripheral blood, and migration and adhesion in the inflammatory lesions.32 33 M-CSF13 14 and c-fms15 16 are expressed in the atheroma, and modified LDL can induce M-CSF gene transcription in endothelial cells in vitro.34 35 Smith et al19 and Quiao et al20 crossed apoE-deficient mice with op/op mice and found that atherogenesis was delayed in these "double knockout mice." However, it might be difficult to inquire about the dynamic response of M-CSF/c-fms and monocytes/macrophages during atherogenesis in these studies because inborn modification in M-CSF gene precedes atherosclerosis initiation.
To circumvent this problem, we used a new approach to administer to
adult apoE-deficient mice the anti–c-fms mAb AFS98 and
dissected the complicated mechanism of atherogenesis by blocking the
M-CSF/c-fms pathway in adult mice (Figure 2). As
demonstrated in Figure 3, a and c, continuous AFS98
administration resulted in marked suppression of fatty streak formation
in apoE-deficient mice. Quantitative analyses showed that AFS98
caused reduction of atheroma formation by 70% (Figure 4). This preventive effect was mediated by the decrease in the
number of monocyte/macrophages in the intima of the vessel wall
(Figure 3d). To confirm that the effect was specific for
anti–c-fms antibody, we conducted additional experiments.
Flow cytometric analysis reveals that AFS98 could recognize
c-fms on the peritoneal macrophages from
apoE-deficient mice (Figure 1, a and b). Since the
isotype-matched irrelevant rat IgG failed to suppress atherogenesis in
apoE-deficient mice (Figure 5, a and b), the preventive effect
of AFS98 was due to the selective blockade of the
M-CSF/c-fms pathway, which could then decrease the number of
monocytes/macrophages in the vessel wall. In this study, we
assessed atherosclerosis by examining the aortic root.
Although the lesion severity in the aortic root correlates well to that
in the entire aorta,36 mechanical shear stress and
other insults could be related to atherogenesis in these
mice.37 Therefore, further investigation should be done
with regard to assessment in the entire aortic lesions.
Interestingly, this preventive effect of AFS98 on atherogenesis in
apoE-deficient mice was not associated with the depletion of
circulating monocytes (Table). It is compatible to the latest
report by Rajavashisth et al38 in which heterozygous
op mutation reduces atherosclerosis in LDL
receptor–deficient mice without severe reduction of circulating
monocytes. We reported previously that administration of 2 mg of AFS98
to mice had no effect on the production of macrophage
colony-forming unit in the bone marrow.23 It
is therefore conceivable that AFS98 at the dose that we used had little
suppressive effect on hematopoiesis in the bone marrow, whereas it was
still sufficient to block the M-CSF/c-fms pathway in the
vessel walls.
We next conducted protocol B to test whether AFS98 had a protective
effect once the lesions had been accomplished. After administration of
AFS98 to the mice fed a high-fat diet during the "late" period (12
to 18 weeks), little effect on oil red O–stained lesion size was
observed (Figure 6a). As far as we could examine, we could not
observe a significant difference in staining pattern of
macrophages or smooth muscle cells between the mice given AFS98
and control mice (Figure 6, c through f), as was seen in
protocol A (Figure 3). As AFS98 staining was found in these
atheromatous lesions by immunohistochemistry (Figure 6g), it is unlikely that the antibody could not enter the
appropriate site. These observations suggest that antibody AFS98 might
have more potent effects on the early events of atherogenesis such as
monocyte migration into the vessel wall and their conversion into
macrophages.
These results taken together reveal that macrophages are most potently involved in initial or early events of atherogenesis, which would be followed by infiltration of other cells. Our current data suggest that macrophages not only appear in the early atherosclerotic lesion but also give rise to subsequent molecular and cellular chain reactions. Therefore, macrophage-specific cellular ablation in the initial phase of atherosclerosis would prevent subsequent fatty streak formation. Recent studies showed that T and B lymphocytes play a minor role in atherosclerotic plaque formation in apoE-deficient mice with targeted disruption of recombinase activator gene (Rag)-131 or Rag-2.32 These studies corroborate our data that suggest the pivotal role of monocyte/macrophage cell lineage in early atherogenesis.
In summary, we demonstrated that the monocyte/macrophage is crucial in initiation and progression of atheromatous lesions and that the M-CSF/c-fms pathway plays a central role in the differentiation, proliferation, and survival of this cell lineage. Provided that c-fms antagonists could be administered and delivered to the vessel walls without considerable effect on the hematopoietic system or bone growth, this could provide us with a unique site-specific therapeutic approach to protect against atherogenesis in the future.
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Acknowledgments |
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This research was supported by Ministry of Education, Science, Sports, and Culture of Japan research grants 04263104, 054040439, 05557052, 04304051, and 08407026; International Scientific Research Program grants 05044163, 07044254, and 09044293 from the Japanese Ministry of Education, Science, Sports, and Culture; a research grant for health sciences from the Japanese Ministry of Health and Welfare; grants 5A-2 and A8-1 for cardiovascular diseases from the Japanese Ministry of Health and Welfare; Grants-in-Aid for Scientific Research on Priority Areas 09281103 and 09281104; Grant-in-Aid for Creative Basic Research 09 NP 0601; the HMG-CoA Reductase Research Fund; the Japanese Foundation of Metabolism and Diseases; Takeda Medical Research Foundation; and Ono Medical Research Foundation. We thank Dr Yasunobu Takakura (Kumamoto University) for his helpful advice and Kyoko Yokoyama for technical assistance.
Received September 18, 1998; revision received November 10, 1998; accepted November 23, 1998.
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