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1 From the Department of Ophthalmology and Visual Sciences, Graduate School of Medicine, Kyoto University; and the 2 Department of Ophthalmology, Nagoya City University Medical School, Japan.
Abstract
PURPOSE. To investigate the distribution of inflammatory mediators such as
interleukin (IL)-1ß and tumor necrosis factor (TNF)-
and
angiogenic cytokines such as vascular endothelial growth factor (VEGF)
and to identify their cellular source in surgically excised choroidal
neovascular membranes (CNVMs) of various ORIGINS. METHODS. Immunoperoxidase staining was performed on paraffin-embedded sections
of 11 surgically excised CNVMs to identify cellular distribution and
localization of cytokines. Immunofluorescent double staining was
performed to detect the cellular source of CYTOKINES. RESULTS. Cytokeratin-positive cells were detected in the RPE layer, in stromal
cells, and around neovascular vessels. Macrophages identified by their
cellular marker CD68 showed almost the same distribution as
cytokeratin-positive cells, although they were most prominent in the
stroma. A substantial number of neovascular vessels were also
immunoreactive to IL-1ß and TNF-. Immunofluorescent double
staining revealed that the RPE layers immunopositive for cytokeratin
were also immunopositive for all cytokines, whereas stromal cells
immunostained for CD68 were positive for IL-1ß and TNF-, but not
for VEGF. CONCLUSIONS. These results indicate that IL-1ß and TNF- secreted by macrophages
may promote, at least in part, angiogenesis in CNVMs by stimulating
VEGF production in RPE cells.
Subfoveal neovascularization is a severe sight-threatening complication of various macular diseases, including age-related macular degeneration (ARMD). Recent immunohistochemical studies on surgically removed choroidal neovascular membranes (CNVMs) have implicated a variety of angiogenic factors.1 2 3 One of the candidate agents for angiogenesis is vascular endothelial growth factor (VEGF), which has been shown to have remarkable potency to induce specific proliferation of endothelial cells4 5 and to increase vascular permeability.6 Moreover, this cytokine has been implicated also in pathologic angiogenesis, including tumor growth,7 8 and in a variety of ocular disorders, such as proliferative diabetic retinopathy, central retinal vein occlusion, and retinoblastoma.9 10 Cell types that have been reported to be immunopositive for VEGF in ocular tissue are retinal pigment epithelial (RPE) cells under physiological conditions11 and glial cells, vascular endothelial cells, fibroblasts, and RPE cells under pathophysiological conditions.2 12 Hypoxia has been shown to be the major stimulator of VEGF induction in various cell types.7 11 13 14 15 Although ischemia has been suggested to be the pathogenic feature responsible in part for VEGF production in ARMD,16 17 stimuli for induction of VEGF in CNVMs remains to be elucidated, because ischemia alone cannot account for all the ocular diseases that lead to the formation of CNVMs. Furthermore, a recent study indicated that VEGF expression can precede retinal nonperfusion and neovascularization.18
Macrophages produce various angiogenic cytokines, including tumor
necrosis factor (TNF)-, interleukin (IL)-1, basic fibroblast growth
factor (bFGF), VEGF, and transforming growth factor
(TGF)-ß,19
20
21
and thus play a key role in angiogenesis.
This concept is further supported by recent studies showing that
chemoattractant of monocytes promotes angiogenesis22
and
that accumulation of macrophages significantly correlates with the
number of newly formed vessels after vascular occlusion.23
In spite of their paucity in normal retina, macrophages are thought to
interact intimately with RPE cells under pathologic conditions, because
they are seen in proximity to RPE cells in various ocular diseases,
including proliferative vitreoretinopathy and the retinopathy of
acquired immune deficiency syndrome and in animal models of
experimental autoimmune uveitis.24
25
26
Although the
involvement of macrophages and other inflammatory cells has been
identified in CNVM,1
27
28
little is known about their
roles other than mediation of inflammation.
We hypothesized that macrophages in CNVMs may exert some effects on
production of VEGF by RPE cells and thereby initiate or contribute, at
least in part, to choroidal neovascularization. Accordingly, we first
performed immunohistochemical studies on the cellular distribution of
RPE cells and macrophages and also on the localization of VEGF as an
angiogenic factor and on IL-1ß and TNF- as presumably
macrophage-derived cytokines. To determine the contribution to
angiogenesis by macrophages, immunofluorescent double staining was used
to confirm the overlap between cellular components and cytokines.
Materials and Methods
Clinical Characteristics
Specimens were obtained from 11 eyes of 10 patients. Their ages
ranged from 34 to 74 years (59.8 ± 4.3 years, mean ± SD), at the time
of vitrectomy. CNVMs of several origins were obtained: five ARMD, three
myopia, two angioid streaks, and one idiopathic choroidal
neovascularization (Table 1)
. Informed consent for the surgical procedure and for the
use of excised tissue was obtained from all patients. All procedures
followed the tenets of the Declaration of Helsinki, and institutional
human experimentation committee approval was obtained for the study.
Vitrectomy was performed according to the technique described
previously.29
Clinical characteristics of all patients are
presented in Table 1 . The size of the CNVM in relation to optic disc
diameter was determined by measurements made on the preoperative
fluorescein angiogram. None of the patients had undergone foveal laser
photocoagulation.
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Immunohistochemistry
For immunohistochemical studies, all incubation steps were
performed in a moist chamber, and rinses were performed by immersing
the slides in a PBS bath. Sections were rehydrated with a graded series
of alcohol and rinsed with PBS. Hydrogen peroxide-methanol (0.3%) was
applied to each specimen for 10 minutes to block endogenous peroxide
activity. After incubating with blocking serum for 20 minutes, the
slides were incubated with primary antibodies for 30 minutes, washed
again with PBS for 10 minutes, and then incubated with biotinylated
secondary antibody for 30 minutes. Sections were rinsed in PBS for 10
minutes, incubated with avidin-conjugated alkaline phosphatase for 30
minutes, and then washed again with PBS. A standard indirect
immunoperoxidase protocol using a kit (Elite ABC; Vector Laboratories,
Burlingame, CA) were performed with diaminobenzidine tetrahydrochloride
(DAB; Dako) as the substrate. Finally, the slides were rinsed with tap
water for 5 minutes, dehydrated through a graded series of alcohol, and
then coverslipped with xylene-based permanent mounting medium.
Hematoxylin and eosin staining was also performed on adjacent sections
to evaluate general pathologic changes.
The procedure of double immunofluorescence staining was similar for peroxidase immunostaining except that sections were incubated with primary antibodies overnight at 4°C, followed by 4 hours of incubation with fluorescent dye–conjugated secondary antibodies at room temperature. Bleaching to remove endogenous peroxide was not performed on any slides. A commercial mounting medium (Vecta Shield; Vector Laboratories) was used. Slides were viewed and photographed in an inverted high-resolution laser-scanning microscope (model LSM 410; Carl Zeiss, Oberkochen, Germany).
To study cell distribution, monoclonal mouse antibodies against
cytokeratin (anti-pancytokeratin, 1:100 dilution; Sigma, St. Louis, MO)
and CD68 (1:50 dilution; Elm, Rome, Italy) were used to visualize RPE
cells and macrophages, respectively. Rabbit polyclonal antibodies
against VEGF (1:200 dilution; Santa Cruz Biotechnology, Santa Cruz,
CA), IL-1ß (1:300 dilution; Endogen, Woburn, MA), and TNF- (1:200
dilution; Endogen) were used to detect cytokines.
Fluorescein-isothiocyanate (FITC)-coupled rabbit anti-mouse antibody
and tetra-methylrhodamine isothiocyanate isomer R
(TRITC)-coupled goat anti-rabbit antibody (both 1:40 dilution;
Dako) were used as the detection system in immunofluorescent staining.
All antibody concentrations were determined individually on appropriate
positive control tissues. Negative control slides were made by
substituting primary antibody with an irrelevant primary antibody of
the same isotype.
Results
Immunohistochemical Study
All specimens contained a partially intact monolayer of RPE cells
located on one side of the CNVMs (Figs. 1
A,
2 A). Other cell types, morphologically presumed to be fibroblasts and
macrophages, were also observed in the stroma, in varying numbers. The
extent of neovascularization and of fibrosis differed among specimens
(Table 2) (Table 2)
.
Neovascularization was more prominent than fibrosis in 6 of the 11
membranes.
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in the RPE monolayer was
more prominent than that of IL-1ß. Uniform immunostaining was also
observed in the neovascular vessels (Figs. 1F
2F)
. Again, no
cause-specific distribution was observed in the immunostaining for
these cytokines.
Immunofluorescent Double Staining
Immunofluorescent double staining was performed to confirm
further the cellular source of cytokines. Most of the
cytokeratin-positive cells in the RPE monolayer were also
immunoreactive to VEGF (Figs. 3A
3B)
. A similar pattern of staining between cytokeratin-positive cells
and cytokine-positive cells was also observed with both IL-1ß and
TNF- (Figs. 3C
3D
3E
3F)
. Some stromal cells immunopositive for
CD68 were found to be stained for IL-1ß and TNF- (Figs. 4A
4B
4C
4D)
. However, no overlap was observed by double staining for
CD68 and VEGF (Fig. 4E)
.
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The stroma of ARMD-related CNVMs is composed of various cell types, including RPE cells, glial cells, fibroblasts, myofibroblasts, vascular endothelial cells, pericytes, macrophages, and lymphocytes.2 3 27 28 30 31 32 33 Our results on cellular distribution and VEGF localization, revealed by immunohistochemical techniques, are in agreement with these previous reports. Because RPE cells in CNVMs have been shown to be immunoreactive to various types of angiogenic cytokines, including VEGF, acidic or bFGF, and TGF-ß, they may be one of the most potent cell components for angiogenesis in CNVM.1 2 3 bFGF has substantial immunoreactivity in both normal retina34 and CNVMs, and has a remarkable potency to promote proliferation of endothelial cells35 ; however, it is not likely to be the primary inducer of neovascularization, because it has no signal sequence for secretion, and its mitogenic activity is not endothelial cell specific.36 37 It is thought to be only after tissue damage progresses to some extent, which facilitates intracellular cytokines to act in a paracrine manner, that FGF can exert its angiogenic effects.38 39 40 Although TGF-ß, similar to bFGF, also shows detectable immunopositivity in normal ocular tissue and CNVMs3 41 and is angiogenic in vivo,42 possible roles for this cytokine in CNVMs remain to be elucidated, because it has a direct inhibitory effect on endothelial proliferation in vitro.43
In contrast to bFGF and TGF-ß, VEGF is an endothelial cell–specific mitogen and is considered to be one of the major inducers of angiogenesis both in vitro and in vivo.4 5 8 9 VEGF has been shown to be secreted by various cell types under hypoxic conditions,7 10 11 13 14 44 45 and four isotypes are produced by alternative splicing of mRNA from one gene.46 Previous studies have shown that RPE cells, endothelial cells, and fibroblast-like cells are VEGF-positive in ARMD-related CNVMs.1 2 12 Because only minimal VEGF immunostaining has been reported to be observed in normal RPE cells, our data demonstrating extensive overlap of staining for VEGF and RPE cells may suggest that VEGF is a candidate for angiogenesis in CNVMs, at least for cytokines associated with RPE cells. Moreover, recent studies showing that VEGF promotes proliferation of RPE cells in an autocrine manner may indicate that RPE cells in CNVMs can initiate a self-amplifying circuit through VEGF production, and the considerable amount of RPE cell–derived VEGF may eventually lead to pathologic angiogenesis.47
Monocytes produce a variety of cytokines and are one of the most common
cell types in CNVMs.28
Little is known, however, about
their roles other than as inflammatory mediators. Monocyte-conditioned
medium can induce morphologic changes in RPE cells and, when
prestimulated with lipopolysaccharide, can also elicit a marked
increase in mRNA of cytokines such as IL-1ß, IL-6, IL-8, and
macrophage colony-stimulating factor.48
Moreover,
experimental animal models of uveitis49
50
can be created
using some of these peptides. Because the promotion of cytokine mRNA
expression induced by monocyte-conditioned medium is completely
suppressed by using the neutralizing antibodies to IL-1 and TNF- in
combination, macrophages in ocular diseases may affect RPE cells
primarily through production of these two cytokines.48
A
previous immunohistochemical study suggested that there was IL-1
secretion by macrophages in the experimental model of laser
photocoagulation-induced CNVM.51
Because recent studies
have shown that both IL-1ß and TNF- stimulate VEGF
production,52
53
our results of immunofluorescent double
staining, which demonstrated that some macrophages in CNVMs were
immuoreactive to both IL-1ß and TNF-, may suggest an indirect
angiogenic role of macrophages in CNVMs. By using human RPE cells, we
also confirmed that both IL-1ß and TNF- increased VEGF mRNA
expression, which is consistent with these studies (data not shown).
Accordingly, the abundance of VEGF in the RPE monolayer demonstrated by
both immunoperoxidase staining and immunofluorescence double staining
may indicate the production of VEGF by RPE cells, induced at least
partly by macrophages. In regard to VEGF production by macrophages,
although we did not observe any colocalization of this cell type with
VEGF by immunofluorescent double staining in CNVMs, because macrophages
have been reported to produce VEGF in pigs and mice,19
we
cannot entirely exclude the possibility. A possible explanation for
this may be that macrophages in CNVMs are not sufficiently activated
for VEGF production, because activation is prerequisite for VEGF
production by this cell type.19
However, further in vitro
studies using human macrophages are required to clarify this point.
The present study also showed definite immunoreactivity of RPE cells to
both IL-1ß and TNF-, in addition to VEGF. A previous study has
shown that only IL-1ß mRNA expression but not protein production by
RPE cells increases in response to exogenous IL-1ß and
TNF-.54
This apparent paradox may be explained by the
possibility that a second signal, not found in the in vitro study, was
required for IL-1ß secretion in vivo. Otherwise, because protein
secretion of IL-1ß and TNF- has not been demonstrated in RPE cells
in vitro54
and the method in the present study detected
protein itself but not mRNA, the immunoreactivity detected in our study
may not necessarily mean synthesis by this cell type and may only
reflect binding of these cytokines to RPE cells.
The uniform immunostaining of IL-1ß and TNF- was also observed in
neovascular vessels. Because both IL-1ß and TNF- have been
reported to be angiogenic in vivo,55
56
57
this may indicate
a more direct pathway, not only through upregulation of VEGF in RPE
cells, for these two cytokines to exert effects on angiogenesis in
CNVMs. Interleukin-1 is secreted by several types of cells, including
endothelial cells, smooth muscle cells, and macrophages58
and is capable of inducing marked ocular neovascularization in
vivo.55
TNF- is definitely an angiogenic factor in
vivo57
and mediates adhesion and activation of additional
monocytes through upregulation of adhesive molecules on both
endothelial cells and monocytes, and by upregulation of
granulocyte–macrophage colony-stimulating factor.59
60
However, both cytokines also have an inhibitory effect on proliferation
of endothelial cells in vitro.61
62
Consequently, because
both IL-1ß and TNF- have complex angiogenic effects, additional
study is required to elucidate their exact roles in relation to
angiogenesis in CNVMs.
Recent studies of ARMD, presumed ocular histoplasmosis, and myopia suggest that CNVMs represent a stereotypic and nonspecific response, regardless of underlying diseases.63 64 Little is known at present about the pathologic features of CNVMs derived from diseases other than ARMD. Our results showed that both cellular localization and cytokine distribution did not correlate significantly with the cause of CNVMs. This may further support the concept that CNVMs represent a common pathologic condition irrespective of the underlying diseases. However, an interesting correlation was observed between the extent of staining for cytokeratin and neovascularization, which may provide evidence of an angiogenic role of RPE cells in CNVMs, as suggested by previous studies.1 2 Moreover, we also demonstrated the same tendency in the case of macrophages.
In summary, the present study provides evidence that macrophages in
CNVMs secrete both IL-1ß and TNF- and thereby contribute greatly
to the development of neovascularization through triggering VEGF
production by RPE cells. Our data also suggest the stereotypic
pathologic conditions underlying the formation of CNVMs, regardless of
cause.
Footnotes
Reprint requests: Hitoshi Takagi, Department of Ophthalmology and Visual Sciences, Graduate School of Medicine, Kyoto University, 54 Shogoinkawara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
Supported by grants-in-aid for scientific research from the Ministry of Education and the Ministry of Health and Welfare of the Japanese Government and by the Japan National Society for Prevention of Blindness, Tokyo.
Submitted for publication October 30, 1998; revised March 8, 1999; accepted April 29, 1999.
Proprietary interest category: N.
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P. Yang, J. L. Wiser, J. J. Peairs, J. N. Ebright, Z. J. Zavodni, C. Bowes Rickman, and G. J. Jaffe Human RPE Expression of Cell Survival Factors Invest. Ophthalmol. Vis. Sci., May 1, 2005; 46(5): 1755 - 1764. [Abstract] [Full Text] [PDF]
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M. Honjo, T. Sawamura, J. Hinagata, K. Nakamura, N. Sanada, H. Tanihara, Y. Honda, and J. Kiryu Expression of LOX-1, an Oxidized Low-Density Lipoprotein Receptor, in Choroidal Neovascularization Arch Ophthalmol, December 1, 2004; 122(12): 1873 - 1876. [Full Text] [PDF]
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A A Okada, T Wakabayashi, E Kojima, Y Asano, and T Hida Trans-Tenon's retrobulbar triamcinolone infusion for small choroidal neovascularisation Br. J. Ophthalmol., August 1, 2004; 88(8): 1097 - 1098. [Full Text] [PDF]
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P. Yang, B. S. McKay, J. B. Allen, and G. J. Jaffe Effect of NF-{kappa}B Inhibition on TNF-{alpha}-Induced Apoptosis in Human RPE Cells Invest. Ophthalmol. Vis. Sci., July 1, 2004; 45(7): 2438 - 2446. [Abstract] [Full Text] [PDF]
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S. W. Cousins, D. G. Espinosa-Heidmann, and K. G. Csaky Monocyte Activation in Patients With Age-Related Macular Degeneration: A Biomarker of Risk for Choroidal Neovascularization? Arch Ophthalmol, July 1, 2004; 122(7): 1013 - 1018. [Abstract] [Full Text] [PDF]
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M. A. Zarbin Current Concepts in the Pathogenesis of Age-Related Macular Degeneration Arch Ophthalmol, April 1, 2004; 122(4): 598 - 614. [Abstract] [Full Text] [PDF]
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E. Sakurai, A. Anand, B. K. Ambati, N. van Rooijen, and J. Ambati Macrophage Depletion Inhibits Experimental Choroidal Neovascularization Invest. Ophthalmol. Vis. Sci., August 1, 2003; 44(8): 3578 - 3585. [Abstract] [Full Text] [PDF]
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D. G. Espinosa-Heidmann, I. J. Suner, E. P. Hernandez, D. Monroy, K. G. Csaky, and S. W. Cousins Macrophage Depletion Diminishes Lesion Size and Severity in Experimental Choroidal Neovascularization Invest. Ophthalmol. Vis. Sci., August 1, 2003; 44(8): 3586 - 3592. [Abstract] [Full Text] [PDF]
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 C. Tsutsumi, K.-H. Sonoda, K. Egashira, H. Qiao, T. Hisatomi, S. Nakao, M. Ishibashi, I. F. Charo, T. Sakamoto, T. Murata, et al. The critical role of ocular-infiltrating macrophages in the development of choroidal neovascularization J. Leukoc. Biol., July 1, 2003; 74(1): 25 - 32. [Abstract] [Full Text] [PDF]
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E. Sakurai, H. Taguchi, A. Anand, B. K. Ambati, E. S. Gragoudas, J. W. Miller, A. P. Adamis, and J. Ambati Targeted Disruption of the CD18 or ICAM-1 Gene Inhibits Choroidal Neovascularization Invest. Ophthalmol. Vis. Sci., June 1, 2003; 44(6): 2743 - 2749. [Abstract] [Full Text] [PDF]
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 V. Lambert, C. Munaut, M. Jost, A. Noel, Z. Werb, J.-M. Foidart, and J.-M. Rakic Matrix Metalloproteinase-9 Contributes to Choroidal Neovascularization Am. J. Pathol., October 1, 2002; 161(4): 1247 - 1253. [Abstract] [Full Text] [PDF]
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P. L. Penfold, L. Wen, M. C. Madigan, N. J. C. King, and J. M. Provis Modulation of Permeability and Adhesion Molecule Expression by Human Choroidal Endothelial Cells Invest. Ophthalmol. Vis. Sci., September 1, 2002; 43(9): 3125 - 3130. [Abstract] [Full Text] [PDF]
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D. G. Espinosa-Heidmann, I. Suner, E. P. Hernandez, W. D. Frazier, K. G. Csaky, and S. W. Cousins Age as an Independent Risk Factor for Severity of Experimental Choroidal Neovascularization Invest. Ophthalmol. Vis. Sci., May 1, 2002; 43(5): 1567 - 1573. [Abstract] [Full Text] [PDF]
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D N PARMAR, R H Y ASARIA, P LUTHERT, and D G CHARTERIS Choroidal neovascularisation at a demarcation line: an immunopathological study Br. J. Ophthalmol., August 1, 2000; 84(8): 928a - 928. [Full Text]
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