Published online before print April 1, 2004, doi: 10.1161/01.ATV.0000127025.48140.a3
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© 2004 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Lack of Interleukin-1 Receptor Antagonist Modulates Plaque Composition in Apolipoprotein E–Deficient Mice
From Internal Medicine I (K.I., S.S., N.I., K.M., M.K., F.O.), National Defense Medical College, Tokorozawa, Japan; and the Center for Experimental Medicine (T.M., Y.I.), Institute of Medical Science, University of Tokyo, Japan.
Correspondence to Dr Kikuo Isoda, Internal Medicine I, National Defense Medical College, 3-2, Namiki, Tokorozawa, Saitama, 359-8513, Japan. E-mail isoda{at}me.ndmc.ac.jp
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Abstract |
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Objective— Interleukin (IL)-1 plays an important role in atherosclerosis. IL-1 receptor antagonist (IL-1Ra) is an endogenous inhibitor of IL-1. However, the role of IL-1Ra in the development of atherosclerosis is poorly understood.
Methods and Results— Mice that lacked IL-1Ra (IL-1Ra–/–) were crossed with apolipoprotein E-deficient (E–/–) mice and formation of atherosclerotic lesions was analyzed after 16 weeks or 32 weeks consumption of a normal chow diet. This study focused on the comparison of atherosclerotic lesion between IL-1Ra+/+/apoE–/– (n=12) and IL-1Ra+/–/apoE–/– mice (n=12), because of the significantly leaner phenotype in IL-1Ra–/–/apoE–/– mice compared with the others. Interestingly, atherosclerotic lesion size in IL-1Ra+/–/apoE–/– mice at age 16 weeks was significantly increased (30%) compared with IL-1Ra+/+/apoE–/– mice (P<0.05). At 32 weeks, the differences of lesion size between these mice failed to achieve statistical significance. However, immunostaining demonstrated an 86% (P<0.0001) increase in the MOMA-2–stained lesion area of IL-1Ra+/–/apoE–/– mice. In addition, 
-actin staining in these lesions was significantly decreased (–15%) compared with those in IL-1Ra+/+/apoE–/– mice (P<0.05).
Conclusions— These results suggest an important role of IL-1Ra in the suppression of lesion development during early atherogenesis and furthermore indicate its role in the modulation of plaque composition.
We investigated the contribution of interleukin-1 receptor antagonist (IL-1Ra) to atherosclerosis by comparing apolipoprotein E single knockout (IL-1Ra+/+/apoE–/–) with IL-1Ra+/–/apoE–/– mice. Immunostaining at age 32 weeks old showed an 86% increase in the MOMA-2–stained lesion area of IL-1Ra+/–/apoE–/–, whereas -actin staining was significantly diminished compared with IL-1Ra+/+/apoE–/– mice.
Key Words: atherosclerosis • immune system • inflammation • interleukins • macrophage
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Introduction |
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Interleukin (IL)-1 plays an important role in immunity, cell damage, and cell proliferation, and is produced and secreted by a variety of cells including those responsible for controlling immunity.1 Cytokines, including IL-1, characteristically form a network in which the production of a specific cytokine leads to serial production of others. In addition to immune reactions, IL-1 has numerous systemic functions, such as promoting fever, stress response, and modulating insulin and lipid metabolism.2–3
Atherogenesis is a complex process in which endothelial cell (EC) and smooth muscle cell (SMC) activation appears to be a central theme.4 IL-1 is produced by ECs and SMCs as well as macrophages/monocytes and hepatocytes.5,6 Furthermore, stimulation and activation of ECs and SMCs by IL-1 causes a wide range of inflammatory processes within the atheroma, such as the enhanced expression of leukocyte adhesion molecules,5,7 clotting factors and inhibitors of fibrinolysis,8 and chemokines,9 as well as increased proliferation of SMCs,4 suggesting a central role for IL-1 in the development of atherosclerosis.
The IL-1 receptor antagonist (IL-1Ra) is a structural homologue of IL-110 that occupies the type I IL-1 receptor with higher affinity and an association rate constant similar to that of IL-111 but is unable to recruit the IL-1 receptor accessory protein, required to mediate intracellular signaling.12,13 Thus activity of IL-1 is counter-regulated by its endogenous inhibitor IL-1Ra.9,14 A previous report showed that IL-1Ra is expressed in ECs and atherosclerotic lesions.15 Recently, we investigated the contribution of IL-1Ra to neointimal formation after injury by comparing IL-1Ra–deficient (IL-1Ra–/–) mice with wild-type (IL-1Ra+/+) mice.16 Intimal thickness and the intima to media ratio were significantly elevated in the IL-1Ra–/– mice compared with the IL-1Ra+/+ mice. Immunostaining for IL-1Ra revealed that IL-1Ra protein was indeed expressed in the endothelium as well as inflammatory cells of the adventitia in IL-1Ra+/+ mice, but was absent in IL-1Ra–/– mice. These results suggested that the IL-1Ra plays an important role in the suppression of neointimal formation after injury. Furthermore, treatment with recombinant IL-1Ra proved an effective therapy for atherosclerosis in apoE-deficient C57BL/6J (apoE–/–) mice.17 Moreover, IL-1Ra gene polymorphism is significantly associated with coronary artery disease.18 These findings suggest that endogenous IL-1Ra may also suppress other occlusive vascular response to injury, such as atherosclerosis.
To directly address the question of whether deficiency of IL-1Ra promotes the development of atherosclerotic lesion and/or can modulate the phenotype of atheroma, we took advantage of IL-1Ra–/– mice generated recently.2 Using hypercholesterolemic apoE–/– mice as an animal model of atherosclerosis, we established three genotypes (IL-1Ra+/+/apoE–/–, IL-1Ra+/–/apoE–/–, and IL-1Ra–/–/apoE–/– mice) by cross-breeding.
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Methods |
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Animals
The generation of IL-1Ra–/– mice used in this study has been described previously.2,16 These mutant mice lacked all 4 isoforms of the IL-1Ra. These mice were backcrossed to the C57BL/6J strain for 8 generations. The apoE–/– mice were obtained from the Jackson Laboratory (Bar Harbor, Me). IL-1Ra–/– mice were crossed with apoE–/– mice and IL-1Ra+/–/apoE+/– mice were backcrossed into the apoE–/– background to produce IL-1Ra+/–/apoE–/– mice. These mice were then intercrossed to generate homozygous apoE–/– mice bearing the IL-1Ra allele combination of either +/+, +/–, or –/–. Screening for apoE was performed by phenotypic assays. Blood specimens were obtained, and apoE deficiency in these mice was detected based on elevation of serum cholesterol as described previously.19 IL-1Ra genotyping was performed by polymerase chain reaction analysis of tail DNA as described previously.2 Throughout the experiment, the mice were fed a normal diet containing 4.6% crude fat with <0.02% cholesterol (CLEA Japan, Inc) to avoid the induction of severe hypercholesterolemia, which has its own consequences on the immune system.20 In this study, we used only male mice to rule out gender differences. The studies were performed according to the protocols approved by the National Defense Medical College Board for Studies in Experimental Animals.
Plasma Lipid Measurements
After fasting for 7 hours, plasma total cholesterol, high-density lipoprotein cholesterol, and triglyceride levels were measured by enzymatic assays as previously described by Hedrick et al.21
Tissue Preparation and Histology
After tail-cuff systolic blood pressure was measured in the mice, male mice at either 16 or 32 weeks of age were euthanized with pentobarbital and perfused with 0.9% NaCl, followed by 4% paraformaldehyde. After perfusion, the aorta was harvested, fixed overnight in 4% paraformaldehyde, embedded in OCT compounds (Tissue-Tek; Sakura Finetechnical Co, Tokyo, Japan) and sectioned (10-µm thickness). All samples were routinely stained with hematoxylin-eosin, Masson trichrome, and oil red O. Immunohistochemistry was performed on each section. Smooth muscle cells were visualized with -smooth muscle cell actin (SMA) staining (Roche), and mouse macrophages/monocytes were visualized with clone MOMA-2 (BioSource International). The sections were visualized using a Vectastain ABC kit (Vector Laboratories) with DAB as the substrate.
Quantification of Atherosclerotic Lesions
Aortic sinus sections were prepared as previously reported.22,23 The area of the lesion was measured using National Institutes of Health (NIH) image 1.55 (public domain software). The values reported represent the mean lesion area from 5 sections for each animal. The quantification of the macrophage and SMCs accumulation in the lesion was determined by calculating the percentage of the MOMA-2 or -SMA, respectively, positive area to the total cross-sectional vessel wall area. The extent of atherosclerosis in the mouse aorta was also determined using an "en face" method.24
Enzyme-Linked Immunosorbent Assay
The serum levels of IL-1ß and IL-1Ra were determined by enzyme-linked immunosorbent assay as described previously.25,26
Analysis of Gene Expression by Real-Time Quantitative Polymerase Chain Reaction
The aortas of 32-week-old mice were dissected and kept in liquid nitrogen. Total RNA was extracted from the aortas using TriReagent (Sigma) and quantity was determined by measuring the absorbance at 260 nm. Reverse-transcription was performed with AMV Reverse Transcriptase XL (Takara Biochemicals, Japan). Quantitative gene expression analysis was performed on an ABI PRISM 7700 machine (Applied Biosystems) using SYBR Green technology. The following oligonucleotide primer pairs were used: IL-1ß sense, 5'- TGG TGT GTG ACG TTC CCA TT-3'; antisense, 5'-CAG CAC GAG GCT TTT TTG TTG-3'; VCAM-1 sense, 5'- TTT GCC GAG CTA AAT TAC AC-3'; antisense, 5'-ATT CTC CCA TAT TGA ACA ACT A-3'; ICAM-1 sense, 5'- TGC GTT TTG GAG CTA GCG GAC CA-3'; antisense, 5'-CGA GGA CCA TAC AGC ACG TGC AG-3'; MCP-1 sense, 5'- GCC CAG CAC CAG CAC CAG-3'; antisense, 5'-GGC ATC ACA GTC CGA GTC ACA C-3'. The optimum number of cycles was set for each gene product with uniform amplification. Each mRNA level was expressed as the ratio to 18S RNA expression.
Statistical Analysis
The results are shown as the mean±SE. Differences between groups were determined using 1-way ANOVA and a multiple comparison test. Two groups were compared using Student t test. A value of P<0.05 was regarded as a significant difference.
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Results |
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The systolic blood pressures were similar among the 3 genotypes at 16 weeks of age (IL-1Ra+/+/apoE–/– mice [n=12]: 87.2±1.2 mm Hg, IL-1Ra+/–/apoE–/– mice [n=12]: 86.6±1.1 mm Hg, IL-1Ra–/–/apoE–/– mice [n=10]: 85.2±0.9 mm Hg; P=NS). However, the body weight of IL-1Ra–/–/apoE–/– mice was significantly less compared with that of either IL-1Ra+/+/apoE–/– or IL-1Ra+/–/apoE–/– mice (Figure I, available online at http://atvb.ahajournals.org). Furthermore, plasma lipid analysis revealed that total cholesterol levels of IL-1Ra–/–/apoE–/– mice were significantly elevated compared with those of the IL-1Ra+/+/apoE–/– mice. Moreover, high-density lipoprotein cholesterol levels of IL-1Ra–/–/apoE–/– mice were lower than those of either IL-1Ra+/+/apoE–/– or IL-1Ra+/–/apoE–/– mice. In contrast, no significant differences in body weights or plasma lipid levels were observed between IL-1Ra+/+/apoE–/– and IL-1Ra+/– /apoE–/– mice. This study therefore compared atherosclerotic lesions between IL-1Ra+/+/apoE–/– and IL-1Ra+/–/apoE–/– mice to exclude differences in body weight or lipid levels as confounding factors. Notably, IL-1Ra serum levels in IL-1Ra+/–/apoE–/– mice (169.4 pg/mL) were approximately half of those in IL-1Ra+/+/apoE–/– mice (332.9 pg/mL) and furthermore the levels of IL-1ß in IL-1Ra+/–/apoE–/– mice tended to be higher compared with those in IL-1Ra+/+/apoE–/– mice (data not shown).
Early Atherogenesis
Aortic root atherosclerotic lesions of IL-1Ra+/–/apoE–/– mice at 16 weeks of age were significantly larger than those in IL-1Ra+/+/apoE–/– mice (Figure II, available online at http://atvb.ahajournals.org). Atherosclerotic lesions were also examined throughout the aorta. The percent of lipid deposits within total aorta was also significantly elevated in IL-1Ra+/–/apoE–/– mice (25.2%±2.1%, n=12) in comparison to IL-1Ra+/+/apoE–/– mice (14.0%±1.2%, n=12; P<0.0001). Neither percent MOMA-2–positive nor -SMA–positive area showed significant difference between these 2 groups (data not shown).
Advanced Atherosclerosis
Lesion size and morphology were also analyzed at 32 weeks of age to determine the effect of IL-1Ra on advanced atherosclerosis. Although lesion size in IL-1Ra+/–/apoE–/– mice tended to be elevated compared with that in IL-1Ra+/+/apoE–/–mice (Figure 1A), the differences did not achieve statistical significance (Figure 1B). En face analysis of the extent of atherosclerosis in the aortas also showed the decrease of difference between IL-1Ra+/–/apoE–/– (38.2%±1.9%, n=12) and IL-1Ra+/+/apoE–/– mice (30.7%±1.8%, n=12; P<0.05). However, immunohistochemical analysis revealed a significant decrease in -SMA stained lesion area IL-1Ra+/–/apoE–/– compared with IL-1Ra+/+/apoE–/– mice (Figure 2A). The percent -SMA positive area was 49.0%±3.7% in IL-1Ra+/+/apoE–/– mice (n=12) versus 41.9%±3.3% in IL-1Ra+/–/apoE–/– mice (n=12) (P<0.05; Figure 2B). These data demonstrate that diminished IL-1Ra expression modulates the lesional -SMA content.
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Notably, IL-1Ra+/+/apoE–/– mice demonstrated features of fibrous plaques, containing necrotic cores and foam cells that were covered by a fibrous cap (Figure 3A). IL-1Ra+/–/apoE–/– mice showed markedly increased lesional macrophage content compared with that of IL-1Ra+/+/apoE–/– mice (Figure 3A). Quantitative analysis of immuno-staining of lesions in the IL-1Ra+/–/apoE–/– mice showed a 1.9-fold increase in MOMA-2 staining compared with that within IL-1Ra+/+/apoE–/– mice (45.6%±3.7% versus 24.4%±2.0%; P<0.0001) (Figure 3B).
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mRNA Levels of Cytokine, Chemokine, and Adhesion Molecules in the Aorta
To investigate the effect of IL-1Ra on the modulation of plaque composition, we next investigated the mRNA expression levels of cytokine, chemokine, and adhesion molecules in the aorta. The mRNA was extracted from the aorta of each mouse at 32 weeks. The results of real-time polymerase chain reaction revealed that the level of IL-1ß mRNA in IL-1Ra+/–/apoE–/– mice was significantly increased by 268% compared with IL-1Ra+/+/apoE–/– mice. Furthermore, the level of MCP-1 mRNA in IL-1Ra+/–/apoE–/– mice was also significantly increased by 442% compared with IL-1Ra+/+/apoE–/– mice. Regarding adhesion molecules, mRNA levels of both ICAM-1 (238%) and VCAM-1 (904%) in IL-1Ra+/–/apoE–/– mice were significantly higher than those in IL-1Ra+/+/apoE–/– mice. These observations suggest that deficiency of IL-1Ra may induce the development of atherosclerosis and accumulation of many macrophages/monocytes in the lesion, possibly by enhancing mRNA expression of IL-1ß, MCP-1, and adhesion molecules.
Effect of Complete IL-1Ra Deficiency on Atherosclerotic Lesion
We also analyzed the extent of atherosclerosis in the aortas of 10 IL-1Ra–/–/apoE–/– mice at 32 weeks of age. The lesion area of IL-1Ra–/–/apoE–/– mice was larger than that of IL-1Ra+/+/apoE–/– mice (Figure 4A and 4B). The percent of lipid deposits within the total aorta was also significantly elevated in IL-1Ra–/–/apoE–/– mice (36.2%±1.6%, n=10) in comparison to IL-1Ra+/+/apoE–/– mice (30.7%±1.8%, n=12; P<0.05). Interestingly, numerous inflammatory cells were observed in the adventitia of IL-1Ra–/–/apoE–/– mice but not of IL-1Ra+/+/apoE–/– mice (Figure 4A through 4D). Masson trichrome-stained section showed stronger destruction of the elastic lamina within the media in IL-1Ra–/–/apoE–/– mice compared with IL-1Ra+/+/apoE–/– mice (Figure 4C and 4D). Immunostaining revealed that the number of -SMA-positive cells in the medial layers of the aorta from IL-1Ra–/–/apoE–/– mice decreased (Figure 4E) but not IL-1Ra+/+/apoE–/– mice (data not shown). Most inflammatory cells in the adventitia of IL-1Ra–/–/apoE–/– mice stained positive for MOMA-2 (Figure 4F). These results suggest that a complete IL-1Ra deficiency may cause not only atherosclerosis but also severe aortitis.
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Discussion |
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In the present study, lowering serum levels of IL-1Ra in IL-1Ra+/–/apoE–/– mice to approximately half of those in IL-1Ra+/+/apoE–/– mice resulted in the significant increase of atherosclerotic lesions formed. These results are supported by a previous study, demonstrating that IL-1Ra–/– mice showed an increase in fatty streak lesion size in the diet-induced atherosclerosis model.27 On the contrary, IL-1Ra–overexpressing apoE–/– mice were protected from aortic lesion formation without changing plasma lipid levels.27 Recently, we demonstrated decreased severity of atherosclerosis in apoE–/– mice deficient for IL-1ß.28 These reports suggest that IL-1 signaling promotes inflammation in the vascular wall, thus contributing to the development of atherosclerosis.
Although the sizes of aortic sinus lesions in IL-1Ra+/–/apoE–/– mice at 32 weeks tended to be larger compared with those in IL-1Ra+/–/apoE–/– mice, the differences failed to achieve statistical significance. However, immunohistochemical analysis revealed a marked increase in the MOMA-2 stained lesion area in IL-1Ra+/–/apoE–/– mice compared with those in IL-1Ra+/+/apoE–/– mice. Furthermore, lesional -SMA staining was significantly decreased. These results suggest that endogenous IL-1Ra has little implications on the suppression of atherosclerotic lesion size in advanced atheroma but plays an important role in early atherogenesis and modulates plaque composition during lesion progression. The present study is the first to demonstrate that IL-1Ra plays an important role in the modulation of advanced plaque composition, because Devlin et al reported about the only early fatty streak lesions in IL-1Ra–/– mice.27 Furthermore, our present findings might have clinical implications. Unstable atherosclerotic plaques are characterized by increased accumulation of macrophages and decreased SMC content, rendering lesions more prone to rupture and subsequent vessel thrombosis than stable plaques with less macrophages and increased accumulation of SMCs.29 Although the murine model of atherosclerosis used here does not allow a direct evaluation of plaque vulnerability to rupture, our results suggest that IL-1Ra deficiency is likely to alter plaque stability.
Our real-time polymerase chain reaction analysis revealed that the lack of IL-1Ra caused the upregulation of IL-1ß, MCP-1, and adhesion molecules at the mRNA levels in the aorta. These changes may contribute to the enhanced accumulation of macrophages/monocytes in the advanced plaque. MCP-1 belongs to the group of CC chemokines that are involved in the recruitment of leukocytes to inflammatory sites and might be critically involved in monocyte/macrophage recruitment to atherosclerotic lesions.30 Furthermore, previous studies have shown that antibody blockade of VCAM-1 significantly reduced monocyte rolling and adhesion in perfused carotid arteries isolated from apoE–/– mice31,32 and that local overexpression of MCP-1 at the vessel wall induces the infiltration of macrophages and formation of atherosclerotic lesions.33 These reports suggest that MCP-1 and adhesion molecules play an important role in the recruitment of monocytes to the arterial intima.
Finally, in the present study atheroma in IL-1Ra–/–/apoE–/– mice displayed inflammation of the adventitia. These results are supported by a previous report. Nicklin et al showed that IL-1Ra–/– mice (on the 129/O1a x MF1 background) had aortic inflammation and that provided evidence for the formation of some aneurysm.34 This group suggested that IL-1Ra plays an important role in the suppression of aortic inflammation. Although our IL-1Ra–/– mice on the C57BL/6J background did not show aortic inflammation, IL-1Ra–/–/apoE–/– mice at 32 weeks old had severe aortitis. These results suggest that chronic inflammation caused by atherosclerosis and/or hypercholesterolemia might trigger inflammation in the adventitia in mice deficient for IL-1Ra. Thus, the present findings suggest a novel pathway implicated in the development of aneurysm caused by atherosclerosis and/or hypercholesterolemia, because previous reports demonstrated that adventitial inflammation, induced by hypercholesterolemia and irritants (CaCl2 or thioglycollate), induced the development of aortic aneurysm in rabbits.35 However, further studies are needed to clarify these mechanisms using our IL-1Ra–/–/apoE–/– mice.
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Acknowledgments |
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Acknowledgments
This study was supported in part by a grant from the National Defense Medical College.
Received February 3, 2004; accepted March 17, 2004.
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