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1From the Peking University Eye Centre, Peking University Third Hospital, Beijing, China; and the 2Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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Abstract |
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METHODS. Photoreceptor apoptosis in rd mice at postnatal days (P)8, 10, 12, 14, 16, and 18 was detected by terminal dUTP transferase nick end labeling (TUNEL). Retinal microglia were identified by CD11b antibody. Expression of chemokine mRNA, including monocyte chemoattractant protein (MCP)-1, MCP-3, macrophage inflammatory protein (MIP)-1
, MIP-1ß, regulated on activation normal T-cell expressed and secreted (RANTES), interferon-
-inducible 10-kDa protein (IP-10), and fractalkine in the retina were examined by reverse transcription-polymerase chain reaction (RT-PCR) assay. Production of tumor necrosis factor (TNF)- in the dystrophic retina was studied by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry analysis. Microglial expression of TNF- was determined by double immunolabeling.
RESULTS. Whereas photoreceptor apoptosis in the rd mice started at P10 and reached a peak at P16, activation and migration of microglial cells were observed at P10 and peaked at P14. The expression of MCP-1, MCP-3, MIP-1, MIP-1ß, and RANTES transcripts were noted at P8 and reached a peak at P12. Production of TNF- was noted in the outer nuclear layer (ONL) of the rd mice at P8 and reached a peak at P12. At the peak of microglial activity, TNF- was predominantly expressed in the activated microglial cells in the ONL.
CONCLUSIONS. Activation of microglia, as well as expression of their signaling molecules (chemokines) and microglia-derived toxic factor (TNF-), coincides with or precedes the occurrence of photoreceptor apoptosis, suggesting activated microglia play a major role in retinal degeneration in rd mice. The chemokines MCP-1, MCP-3, MIP-1, MIP-1ß, and RANTES are involved in activation and recruitment of the microglia to the degenerating photoreceptor cell layer. TNF-, produced by the activated microglia, may accentuate the photoreceptor cell death.
In the past decade, increasing attention has been focused on the pathogenic role of microglia in retinal degenerations. Resident microglial cells are found to migrate into the outer nuclear layer (ONL) and subretinal space during the early stage of retinal degeneration in RCS rats4 5 and in light-induced retinal degeneration of murine models.6 Recently, Zeiss and Johnson7 observed the proliferation of microglia in the ONL accompanying early photoreceptor degeneration in rd mice, which confirmed the intimate association between activated microglia and the degenerative process in this animal model. However, the relationship of microglial activation to photoreceptor apoptosis has not been elucidated.
Microglia are resident macrophages and immune cells in the central nervous system (CNS) and retina that are adapted to the specialized microenvironment of neural tissue.8 Activation of microglia occurs rapidly after injury of the CNS and is characterized by changes in the cellular morphology, cell number, cell mobility, and upregulation of surface molecules. Moreover, activated microglia have the potential of producing cytotoxic substances, such as the cytokine tumor necrosis factor (TNF)-, reactive oxidative species, nitric oxide (NO), proteases, and excitatory amino acids that may induce neuronal degeneration.9 10 Activation of microglia has been described in several human neurodegenerative diseases, including Alzheimer’s disease,11 AIDS dementia,11 Parkinson’s disease,12 and glaucoma.13
A chronic inflammatory process has been closely associated with the pathogenesis of neurodegenerative diseases in the CNS.14 15 16 Chemokines and cytokines are immune signaling molecules that cause secondary damage during inflammation and can exaggerate neurodegeneration.17 18 19 In the CNS, microglial activation is thought to be critically important in the neurodegenerative diseases process. Among the "signals" that activate microglia, chemokines are the potential mediators of microglial cell recruitment to the sites of injury.20 Chemokines are the rapidly expanding family of chemotactic cytokines in which there are more than 30 recognized members to date.21 They are subdivided into four distinct groups based on the positions of conserved cysteine residues in their N-terminal sequence: CXC, CC, C, and CX3C chemokines. The CXC or chemokines, such as interleukin (IL)-8, are one of the major families that primarily recruit the neutrophil, whereas CC or ß chemokines, including MCP1–5, MIP-1 and -1ß, and RANTES, among others, belong to the other major subfamily that predominantly acts on monocytes, macrophages, and microglia.21 Elevated expression of ß chemokine members has been reported in many CNS disorders, such as multiple sclerosis (MS),22 cerebral ischemia,23 and ocular inflammations,24 promoting the microglial migration to the site of injury. TNF- is another key proinflammatory factor in the brain25 and the eye.26 TNF-, produced by CNS microglia, has been shown to kill cultured oligodendrocytes27 and is strongly implicated in the pathogenesis of demyelinating diseases such as multiple sclerosis.28 TNF- and other microglia-derived neurotoxins have made microglia become a potential destructive presence in the CNS and retina.
The purpose of this study was to elucidate the role of activated microglia in the photoreceptor apoptosis of rd mice by identifying sequential events and factors associated with microglial activation, migration, and cytotoxicity during retinal degeneration. For this purpose, we observed microglial proliferation and migration during photoreceptor apoptosis, identified the signaling molecules (chemokines) that activated retinal microglia, and detected the cytotoxic cytokine TNF- produced by the activated microglia.
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Materials and Methods |
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Tissue Preparation
After the mice were killed, one of the eyes was enucleated rapidly and fresh-frozen in optimal cutting temperature compound (Tissue-Tek; Sakura Finetek, Tokyo, Japan) in liquid nitrogen and stored at –80°C until sectioning. The tissue blocks were cut vertically at 8 µm through the optic nerve head and ora serrata with a cryostat. The other eye was enucleated and prepared as a retinal wholemount. The globes were dissected behind the ciliary body into anterior and posterior part. The lens and vitreous were carefully removed, and the whole retina was separated from the underlying retinal pigment epithelium and choroid. The retinal wholemount was fixed in cold 100% ethanol for 10 minutes and then placed in PBS in a 24-well tissue culture dish at 4°C until it was used.
TUNEL Assay and Quantitative Analysis
Photoreceptor apoptosis was determined by terminal deoxynucleotide transferase nick end labeling according to the manufacturer’s instructions (Dead End Colorimetric TUNEL System; Promega Corp., Madison, WI). Diaminobenzidine (DAB) was used as color substrate. For quantitative analysis, TUNEL-positive nuclei and total number of photoreceptor nuclei in the ONL per section were counted under 400x magnification (three sections from each eye, three eyes from each age group) by a masked observer. The percentage of TUNEL-positive photoreceptor nuclei to total photoreceptor cells was determined for the whole retina.
Immunohistochemistry and Quantitative Analysis
CD 11b (Mac-1) is a generally used microglia/macrophage marker in the mouse, comparable to OX42 in the rat.29 30 It is one of the first macrophage markers defined by monoclonal antibody31 and has been found to bear significant similarity to F4/80, another universal and widely used mouse macrophage marker.29 32 CD11b antibody recognizes type 3 complement receptor (CR3) of microglia/macrophages. Several studies have shown that CR3 is normally expressed in all microglial cells and is markedly upregulated on activation.33 34 Therefore, CD11b antibody can be used to label both resting and activated microglial cells. In a previous study in our laboratory, Zhang et al.35 used the CD 11b antibody to label mice microglia and considered it an appropriate quantitative microglial marker in a study of retinal injury by light.
In this study, CD11b immunolabeling of the microglia was performed on both retinal sections and wholemounts. Endogenous peroxidase activity was eliminated by incubating the retinas in 3% hydrogen peroxidase in phosphate-buffered saline (PBS) for 15 minutes. Ten percent of goat serum in PBS was used to block nonspecific labeling. The retinal sections were incubated with rat anti-mouse monoclonal CD11b antibody (1:50; Serotec, Ltd., Oxford, UK) at 4°C overnight and were further incubated with secondary antibody biotinylated goat anti-rat IgG (1:200, Vector Laboratories, Burlingame, CA) and streptavidin peroxidase (Histostain Plus kit; Zymed, South San Francisco, CA) for 30 minutes at room temperature. DAB was used as a chromogen. Retinal wholemounts were soaked in 1% Triton-100 in 0.1 M PBS for 1 hour at room temperature before incubation in primary antibodies at 4°C for 24 to 48 hours and then were incubated in secondary antibody for 1 hour at 37°C. Streptavidin peroxidase was conjugated to the secondary antibody for 30 minutes at room temperature. After they were developed in the DAB, the retinal wholemounts were placed on gelatin-coated glass slides with the inner side facing up and air dried at room temperature. Both sections and retinal wholemounts were dehydrated in and ascending ethanol series, immersed in xylene, and coverslipped. Negative controls were performed by replacing the primary antibody with PBS or normal nonimmunized rat serum to ensure the absence of nonspecific staining.
The morphology and distribution of CD11b-labeled cells was assessed by light microscopy in both retinal sections and wholemounts from three eyes of each age group. The positively labeled cells in the different layers of retinal wholemounts were observed by adjusting the focus of the microscope. The average density of positively labeled cells (mean ± SD cells/ mm2) in the outer retina (ONL and between the photoreceptor elements) was calculated for each eye and for each age group at comparable retinal locations, with a 20x objective lens.
For immunolabeling of TNF-, cryosections were blocked with 10% horse serum in PBS for 30 minutes and then incubated with primary goat anti-mouse polyclonal antibody TNF- (1:400; Santa Cruz Biochemicals, Inc., Santa Cruz, CA) at 4°C overnight. After the sections were washed in PBS for 30 minutes, the secondary antibody horse anti-goat IgG conjugated with FITC (1:100, Jackson ImmunoResearch Laboratories, West Grove, PA) was added for 45 minutes at room temperature. Negative control experiments were performed by replacing the primary antibody with PBS or normal nonimmunized goat serum. For double labeling, the tissue sections were incubated with two primary antibodies from different species (CD11b antibody from rat and TNF- antibody from goat) at 4°C overnight. After the sections were washed in PBS for 30 minutes, they were incubated with their corresponding secondary antibodies, conjugated with either cy3 (1:1000; Jackson ImmunoResearch Laboratory) or FITC (1:100) for 45 minutes at room temperature. The sections were observed with a confocal laser scanning microscope (TCS-NT; Leica, Wetzlar, Germany) with 568-nm filter for cy3 red and 488-nm filter for FITC green. Images were captured and postprocessed by digital photography (DXL-5500; Sony Tokyo, Japan) and confocal software (Leica).
Semiquantitative Reverse Transcription–Polymerase Chain Reaction
A semiquantitative reverse transcription–polymerase chain reaction (RT-PCR) assay was performed to measure the expression levels of chemokine mRNA transcripts in the whole retina. Total RNA was prepared from freshly dissected retinas of rd and control eyes as follows. Twelve retinas of each age group were solubilized (1 mL TRIzol reagent; Invitrogen Co., Carlsbad, CA) in a tissue homogenizer. RNA was extracted with chloroform, precipitated with isopropyl alcohol, washed by 75% ethanol and resuspended in RNase-free water, according to the manufacturer’s instructions. The total RNA was then used for cDNA synthesis. A reverse transcriptase system (Superscript II RNase H–; Invitrogen) with oligo-dT was used according to the manufacturer’s protocol. PCR was performed with Platinum Taq DNA Polymerase (Invitrogen). The 25-µL reaction mixture consisted of 1 µL cDNA, 1 µL of sense and anti-sense primer, 200 µM of each deoxynucleotide, 2.5 µL 10x PCR buffer (with 25 mM MgCl2), and 0.5 U DNA Polymerase (Platinum Taq; Invitrogen). Conditions for each chemokine amplification were as follows: preheating for 5 minutes at 94°C; 35 cycles of 30 seconds’ denaturation (94°C), annealing, and extension (72°C); final extension for 7 minutes at 72°C. Annealing temperatures were 56°C for ß-actin and IP-10, 57°C for RANTES and fractalkine, 58°C for MCP-3, 62°C for MIP-1ß, and 63°C for MCP-1 and MIP-1. The primer sequences used in the experiments are listed in Table 1 . An equal volume of PCR products from each age group was separated on 1% to 2% arose gel containing ethidium bromide, and fluorescence bands were digitally captured for analysis of intensity (Quantity One Image Software; Bio-Rad Laboratories, Hercules, CA). Expression of ß-actin was used as an internal control of RNA amount in each age group. Levels of chemokines were expressed as ratios to that of ß-actin.
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by Enzyme-Linked Immunosorbent Assay protein level in the mice retinas was determined by enzyme-linked immunosorbent assay (ELISA) as previously described36 with modifications. Briefly, 8 to 12 retinas of each age group were homogenized in 500 µL cold sterilized PBS buffer with protease inhibitor (100 µg/mL phenylmethylsulfonyl fluoride [PMSF], and 1 µg/mL aprotinin in 0.1 M PBS). The homogenates were centrifuged at 12,000g at 4°C. TNF- in the supernatant was detected with a mouse TNF- ELISA kit, according to the manufacturer’s instructions (R&D Systems, Minneapolis, MN). Protein concentrations of all samples were measured using a bicinchoninic acid (BCA) protein assay kit (Pierce, Rockford, IL) before ELISA, and equivalent amounts of proteins were used for the assay.
Statistical Analysis
The data are presented as the mean ± SD. Statistical significance was assessed with an analysis of variance (one-way ANOVA) followed by the Tukey honest significant difference (HSD) multiple comparisons test. P < 0.05 was considered statistically significant.
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Results |
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, MIP-1ß, and RANTES transcripts increased with the development of photoreceptor cell death in a time-dependent manner. Initially, the expression of MCP-1, MCP-3, MIP-1, MIP-1ß, and RANTES transcripts at P8 were weak, but showed a marked increase at P10 and reached a peak at P12. By P18, the gene expression declined to the basal level. No chemokine was detected in the normal control retinas except RANTES (very weak). The expression of fractalkine was strong in both normal and rd mice retinas in all age groups, without significant difference (P > 0.05). IP-10 transcript expression was not detected either in normal or rd mice retinas.
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in the rd Retinas in the rd and normal retinas during photoreceptor degeneration. As shown in Figure 4A , production levels of TNF- in the rd retinas at P8, P10, P12, P14, and P16 were significantly higher than those in the normal control retinas (P < 0.05). In the P8 rd retina, the protein level of TNF- was still comparably low, but it was markedly elevated at P10 and reached a peak at P12. The protein level decreased sharply thereafter until it returned to normal level at P18.
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expression was confirmed by immunohistochemical study. Our study indicated that TNF- immunoreactivity was restricted to the ONL of the rd retinas and was not observed in that of the normal control (Fig. 4B 4C 4D 4E 4F) . Expression of TNF- in the rd retinas at each age group was parallel to the result of ELISA. Double immunolabeling of TNF- and CD11b at the peak of microglial activity (P14) showed expression of TNF- predominantly in the activated microglial cells in the ONL (Fig. 4H 4I 4J) . Only a small portion of TNF- positive labeling was seen in the photoreceptor cells. |
Discussion |
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) and occurrence of photoreceptor apoptosis during the retinal degenerative process of rd mice. The retinal microglia were activated and infiltrated ONL at P10 and reached a peak at P14, whereas photoreceptors apoptosis started at P10 and peaked at P16. Expression of chemokines including MCP-1, MCP-3, MIP-1, MIP-1ß, and RANTES transcripts was observed at P8 and peaked at P12, preceding the onset and peak of the microglial migration. Production of TNF- was noted in the ONL of rd retinas at P8 and reached a peak at P12, preceding the initiation and peak of photoreceptors apoptosis. At the peak of microglial activity (P14), TNF- was predominantly expressed in the microglial cells in the ONL. The above sequential events showed that presence of activated microglia, as well as their signaling molecules and microglia-derived toxic cytokine coincided with or preceded the photoreceptor apoptosis, suggesting that activation of retinal microglia may play a major role in retinal degeneration in rd mice. Retinal microglia are known to play a phagocytotic role in clearing photoreceptor debris in the dystrophic retinas.4 5 6 However, they can also release cytotoxic factors that induce photoreceptor cell death in vitro.37 We hypothesize that in the rd retina, the gene defect in ß-PDE resulting in metabolic disorders promotes the initial injury to the photoreceptors. Diseased photoreceptors produce chemokines to activate and recruit retinal microglial cells to the outer retinal layers. The microglial cells exaggerate photoreceptors’ death by secreting cytotoxic substances, like TNF-, as well as effectively remove the cellular debris.
It has been suggested that activated microglia, having migrated to the photoreceptor cell layer in response to photoreceptor dysfunction or to the debris buildup in the subretinal space, may be the instigator of photoreceptor apoptosis in the RCS rat.5 In contrast, Hughes et al.38 argued that, in the rds mice, a slower retinal degeneration model, microglia were unlikely to be the initiators of photoreceptor death because the peak rate of photoreceptor apoptosis precedes the peak in the number of microglia by at least 5 days, and no nitric oxide production was found at the peak of microglial activity. However, they asserted that although innocent of initiation of photoreceptor cell death, the exuberant microglial response may both potentiate and perpetuate the disease process. In our present study of rd mice, we observed prominent activation and accumulation of microglial cells in the ONL from the earliest time of photoreceptor cell death, consistent with the findings by Zeiss and Johnson.7 Moreover, by closely scrutinizing the temporal relationship between photoreceptor apoptosis and microglial response, we demonstrated in the rd retina, the peak of the microglial activation preceded that of progressive photoreceptor cell apoptosis; and, at this time point, TNF- was predominantly produced by microglia, indicating microglia may be an instigator of photoreceptor cell death in this animal model. Comparison between these studies is difficult because of different animal strains, gene defects, and toxic factors observed. However, the central role of activated microglia in the photoreceptor degeneration is not in doubt.
The MCP family, as well as other ß-chemokine members, are considered to be the principal chemokines involved in the recruitment of monocytes/macrophages to the site of injury and inflammation. In animal models of inherited retinal dystrophy, ß-chemokines may play a similar role in activating and recruiting microglial cells to the outer retinal layers, which is the primary site of retinal degeneration. In our present study of rd mice, the expression of MCP-1, MCP-3, MIP-1, MIP-1ß, and RANTES mRNA transcripts was first noted at P8 and reached a peak at P12, well before the initiation and peak of microglial migration, suggesting a possible causal role of these chemokines in activation and trafficking of the retinal microglial cells to the degenerating photoreceptor cell layer. Besides ß-chemokines, we also examined IP-10 and fractalkine, which belong to CXC (or ) and CX3C chemokines, respectively, and have been shown to contribute to the chemotaxis of microglia/macrophages in some ocular inflammatory conditions.24 39 However, our results suggest that they did not play a significant role during the degenerative process in rd mice. In our experiment, expression of chemokine transcripts was examined by RT-PCR assay, which is a sensitive method for detection of low-abundance mRNA. However, as a quantitative method, conventional RT-PCR suffers from the problems inherent in end-point quantitation of PCR products and is semiquantitative. Real-time PCR, a fluorescence-based technique, can overcome these limitations and provide absolute quantitative results by dynamically and accurately detecting the transcripts.
Elner et al.40 indicated that many retinal cells, including retinal neuron cells, astrocytes, microglia, and infiltrating monocytes had the potential to produce chemokines. In our study, we hypothesized that the chemokines were produced by the diseased photoreceptors as microglial migration was directed toward the diseased photoreceptors. Moreover, in the advanced stage, when most photoreceptor cells had disappeared, microglial activation gradually subsided and microglial migration into the outer retina was diminished. These observations suggest that the chemokines released by the degenerating photoreceptors may correspondingly have been reduced. Microglial cells are reported to produce a wide range of chemokines and cytokines in the CNS. However, they may not be the initial source of chemokines in this study, because the initial and peak production of chemokines preceded the onset and peak of microglial activation. It is possible that chemokines initially released by the damaged photoreceptors attracted microglia to the outer retina, and the microglia secreted more chemokines and amplified the postinjury inflammatory response. Further immunohistochemistry study of chemokine protein will be needed to identify the cell types of chemokine production.
TNF- produced by microglia and damaged neurons are known to play an important role in the neuroinflammatory and neurodegenerative processes in the CNS.25 28 TNF- produced by the retinal microglia was shown to be toxic to the photoreceptor cells in the RCS rats in vitro41 and EAU animal models in vivo.42 Blockade of TNF- synthesis or function by signaling inhibitors or neutralizing antibodies could prevent the development of CNS inflammation and ameliorate the neuronal cell death. Our in vivo study of the rd mice demonstrated that initial and peak production of TNF- preceded the onset and the peak of photoreceptors apoptosis. Double labeling of microglia and TNF- at the peak of microglial activity (P14) showed that activated microglia in the photoreceptor cell layer were the major source of TNF-. Production of TNF- at this time might exert a direct toxic effect on the photoreceptor cells, because it was well before the peak of photoreceptor death. Diseased and apoptotic photoreceptor cells could be another major source of TNF- production, which would account for the observations that both initial and peak production of TNF- preceded the onset and peak of microglial activation, respectively. Besides direct neurotoxicity, TNF- may also exert an indirect destructive effect on neurons through further activation of microglia and promoting their production of NO43 or may contribute to cell death by combining with other reactive oxidative species released by the activated microglia.44 The indirect neurotoxicity of TNF- could be one of the reasons why production of TNF- peaked 2 days before that of microglial activation, but 4 days earlier than photoreceptor apoptosis, which seemed a rather lengthy time.
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Acknowledgements |
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Footnotes |
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Submitted for publication January 30, 2005; revised March 11 and April 7, 2005; accepted April 22, 2005.
Disclosure: H. Zeng, None; X. Zhu, None; C. Zhang, None; L.-P. Yang, None; L. Wu, None; M.O.M. Tso, None
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. 
1734 solely to indicate this fact.
Corresponding author: Mark O. M. Tso, Wilmer Eye Institute, Johns Hopkins Hospital, 457 Wilmer-Woods Building, 600 N. Wolfe Street, Baltimore, MD 21287; matso{at}jhmi.edu.
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