doi: 10.1161/hc5001.100631
(Circulation. 2001;104:3103.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Toll-Like Receptor-4 Is Expressed by Macrophages in Murine and Human Lipid-Rich Atherosclerotic Plaques and Upregulated by Oxidized LDL
From the Atherosclerosis Research Center, Burns and Allen Research Institute, Division of Cardiology (X.H.X., P.K.S., X.-P.X., T.B.R., J.Y., S.K.), the Division of Pediatric Infectious Diseases, Steven Spielberg Pediatric Research Center (E.F., O.E., L.T., M.A.), the Department of Pathology, UCLA School of Medicine (M.C.F.), and the Department of Pathology, Cedars-Sinai Medical Center (D.L.), Los Angeles, Calif.
Correspondence to Moshe Arditi, MD, Cedars-Sinai Medical Center, Division of Pediatric Infectious Diseases, 8700 Beverly Blvd, Room 4220, Los Angeles, CA 90048. E-mail moshe.arditi{at}cshs.org
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Abstract |
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Background— Inflammation is implicated in atherogenesis and plaque disruption. Toll-like receptor 2 (TLR-2) and TLR-4, a human homologue of drosophila Toll, play an important role in the innate and inflammatory signaling responses to microbial agents. To investigate a potential role of these receptors in atherosclerosis, we assessed the expression of TLR-2 and TLR-4 in murine and human atherosclerotic plaques.
Methods and Results— Aortic root lesions of high-fat diet-fed apoE-deficient mice (n=5) and human coronary atherosclerotic plaques (n=9) obtained at autopsy were examined for TLR-4 and TLR-2 expression by immunohistochemistry. Aortic atherosclerotic lesions in all apoE-deficient mice expressed TLR-4, whereas aortic tissue obtained from control C57BL/6J mice showed no TLR-4 expression. All 5 lipid-rich human plaques expressed TRL-4, whereas the 4 fibrous plaques and 4 normal human arteries showed no or minimal expression. Serial sections and double immunostaining showed TLR-4 colocalizing with macrophages both in murine atherosclerotic lesions and at the shoulder region of human coronary artery plaques. In contrast to TLR-4, none of the plaques expressed TLR-2. Furthermore, basal TLR-4 mRNA expression by human monocyte-derived macrophages was upregulated by ox-LDL in vitro.
Conclusions— Our study demonstrates that TLR-4 is preferentially expressed by macrophages in murine and human lipid-rich atherosclerotic lesions, where it may play a role to enhance and sustain the innate immune and inflammatory responses. Moreover, upregulation of TLR-4 in macrophages by oxidized LDL suggests that TLR-4 may provide a potential pathophysiological link between lipids and infection/inflammation and atherosclerosis.
Key Words: receptors • inflammation • cells • atherosclerosis • lipoproteins
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Introduction |
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Experimental work over the past decade has linked inflammation to atherogenesis and plaque disruption.1–4 The precise triggers for inflammation are not known but may include modified lipoproteins and local or distant infections.2 A potential role for infection in the development of atherosclerosis has been considered for several decades, but interest in this topic has recently reemerged because of several recent observations. Accumulating evidence has implicated specific infectious agents, including Chlamydia pneumoniae, in the progression and/or destabilization of atherosclerosis.1–17
Recent studies suggest that chlamydia lipopolysaccharide (LPS) induces foam-cell formation, whereas its heat-shock protein (chlamydia HSP60) induces oxidative modification of LDL.5,18 Chlamydia HSP60 has been implicated in the induction of deleterious immune responses in human chlamydial infection and has been found to colocalize with infiltrating macrophages in the atheroma lesions.19 Collectively, these data support a potential role for C pneumoniae in the development and progression of atherosclerosis and suggest that this organism may indeed play an active role in atheroma development. Available data, however, also underscore the current lack of a complete understanding of the molecular mechanisms that link C pneumoniae infection to innate immunity and trigger the signals for enhanced inflammation and atherogenesis.
LPS, a major component of the outer surface of Gram-negative bacteria, activates the proinflammatory transcription factor nuclear factor (NF)-
B in endothelial cells and macrophages.20,21 Recently, human Toll-like receptor-4 (TLR-4), a human homologue of drosophila Toll, has been identified as the signaling receptor for endotoxin22 as well as human and chlamydial HSP60.23,24
Currently, more than 10 human TLRs have been identified, and at least 10 human homologues of drosophila Toll have been sequenced. Whereas TLR-4 is used by enteric Gram-negative bacteria and LPS, TLR-2 is used by Gram-positive bacterial, mycobacterial, fungal, and spirochetal cell-wall components.25,26 TLRs are evolutionarily conserved innate immune receptors that recognize pathogen-associated molecular patterns and contain a common intracytoplasmic domain that conveys signals by molecules that are shared by interleukin-1 receptor signaling to activate the NF-B pathway and release inflammatory cytokines.21,27 Because TLR-2 and TLR-4 play an important role in the innate immune and inflammatory responses, we investigated the expression of these receptors in murine aortic and human coronary atherosclerotic plaques. Here, we report preferential expression of TLR-4 in lipid-rich and macrophage-infiltrated murine and human atherosclerotic plaques. In vitro studies demonstrated basal expression of TLR-4 by macrophages, which was upregulated by oxidized LDL (ox-LDL). These findings suggest a potential role for TLR-4 in lipid-mediated proinflammatory signaling in atherosclerosis. Because TLR-4 is the receptor that recognizes chlamydial antigens such as chlamydia LPS and HSP60, it may provide a potential molecular link between chronic infection, inflammation, and atherosclerosis.
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Methods |
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Preparation of Mouse Tissue
Apolipoprotein E (apoE)-deficient mice (C57BL/6J strain, 5 weeks old, 18 to 20 g) obtained from Jackson Laboratory (Bar Harbor, Me) (n=5) were fed a high-fat, high-cholesterol (atherogenic) diet containing 42% (wt/wt) fat and 0.15% cholesterol from 6 weeks of age through the duration of the experiment. After anesthesia with eflurane, the mice were euthanized at 26 weeks of age, and their hearts and proximal aortas were excised and embedded in OCT compound (Tissue-Tek), frozen on dry ice, and then stored at -70°C until sectioning. Serial sections 10 µm thick were collected on slides for immunohistochemistry as described earlier.28
Preparation of Human Tissue and Human Monocyte-Derived Macrophages
Human coronary artery specimens from 9 autopsy cases were collected within 24 hours of death, fixed with 10% formalin overnight, and embedded in paraffin. Five of the 9 coronary artery specimens included lipid-rich plaques containing a well-defined lipid core covered by a fibrous cap, and the other 4 of the 9 specimens included fibrous plaques, which contained mostly extracellular matrix without a lipid core. Normal mammary artery specimens were also obtained from 4 additional autopsy cases. Sections 5 µm thick were cut and applied to slides for both hematoxylin-eosin and immunohistochemical staining. Peripheral-blood monocytes were isolated from whole blood of normal human subjects by Ficoll-Paque density gradient centrifugation. Monocyte-derived macrophages were cultured in RPMI 1640 containing 10% FCS, 100 U/mL penicillin, 100 µg/mL streptomycin, and 0.25 µg/mL amphotericin B for 5 days as described earlier.29
Immunohistochemistry
Frozen sections of the apoE-deficient mouse aortic root were fixed with acetone for 5 minutes at room temperature and then immunostained with rabbit anti-hTLR-4 immune serum (1:100, obtained from Dr Ruslan Medzhitov, Yale University) according to the instructions on Dako’s immunostaining kit. Rat anti-mouse macrophage antibodies (1:500, Serotec) were used as macrophage marker. Colors were developed with the Dako AES substrate system. Smooth muscle cells were stained by a mouse anti-actin antibody conjugated with alkaline phosphatase (1:50, Sigma). Colors were developed with a Vector Red Alkaline Phosphatase Substrate Kit I. Rabbit IgG or rabbit serum was used as a negative control.
For human atherosclerotic plaques, after deparaffinization in graded alcohol, sections were immunostained with rabbit anti-human TLR-4 and TLR-2 antiserum (1:100) raised against extracellular peptide domains of TLR-4 and TLR-2 as previously described.21 Preincubation of the anti-TLR-4 antiserum with TLR-4 peptide (FKEIRHKLTLRNNFDLSLNVMKT) was used to demonstrate specificity of the stain, and rabbit IgG or rabbit serum instead of primary antibody was used as negative control.
Double Immunohistochemistry
Double immunostaining of human atherosclerotic plaques was performed with Dako’s Doublestain System kit. After TLR-4 immunostaining, 3,3'-diaminobenzidine was used as the peroxidase chromogenic substrate. Mouse monoclonal anti-human CD68 antibody (360 µg/mL, 1:20 dilution; Dako, Derma) for macrophages and mouse monoclonal anti-human 
-actin antibody (100 µg/mL, 1:100 dilution; Dako, Derma) for smooth muscle cells were used with fast red as the alkaline phosphatase chromogenic substrate.
Preparation and Modification of Lipoproteins
Human native LDL (Sigma) was dialyzed against isotonic PBS (pH 7.4) to remove EDTA by use of Slide-A-Lyzer cassette 10 000 MWCO (Pierce). Ox-LDL was prepared as described previously.30 In brief, oxidation of LDL was performed by incubating 0.1 mg of LDL protein/mL with 5 µmol/L CuSO4 for 24 hours at 37°C. All reagents were endotoxin-free. LPS levels of LDL preparations were confirmed with a chromogenic Limulus assay and contained <0.3 pg of LPS/µg LDL protein. The extent of oxidation of the lipoprotein preparations was determined by the thiobarbituric acid-reactive substance (TBARS) assay.31 The ox-LDL had 20 to 25 nmol/L TBARS/mg cholesterol.
Reverse Transcription-Polymerase Chain Reaction
Total RNA was isolated from resting and native LDL-, ox-LDL-stimulated human monocyte-derived macrophages with an RNA Stat60 isolation reagent (Tel-test "B" Inc) according to the manufacturer’s instructions and treated with RNase-free DNase I. For the reverse transcription (RT) reaction, the MMLV preamplification system (Life Technologies, Inc) was applied. Polymerase chain reaction (PCR) amplification was performed with Taq gold polymerase (Perkin Elmer) for 32 cycles at 95°C for 45 seconds, 54°C for 45 seconds, and 72°C for 1 minute (for TLR-2 and TLR-4). The oligonucleotide primers used for RT-PCR were TLR-2, 5'-GCCAAAGTCTTGATTGATTGG and 5'-TTGAAGTTCTCCAGCTCCTG; for TLR-4, 5'-TGGATACGTTTCCTTATAAG and 5'-GAAATGGAGGCACCCCTTC-5' as described earlier.32 GAPDH primers were obtained from Clontech.
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Results |
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TLR-4 Is Expressed in Atherosclerotic Lesions of ApoE-Deficient Mice
In all 5 apoE-deficient mice, TLR-4 immunoreactivity was observed in the aortic root atherosclerotic lesions, which colocalized with macrophage immunoreactivity (Figure 1). TLR-4 staining was absent in the normal vessels obtained from control C56BL/6J mice. Mouse IgG staining was negative, and preincubation of the tissue sections with the specific peptide against which the anti-TLR-4 antiserum was generated completely blocked the TLR-4 staining in the apoE-deficient vessels, indicating the specific nature of the TLR-4 immunostaining. No TLR-2 immunoreactivity was observed (data not shown) in normal or atherosclerotic lesions.
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TLR-4 Is Expressed in Human Coronary Plaques
The human coronary atherosclerotic plaques were classified into lipid-rich plaques containing a well-defined lipid core covered by a fibrous cap (n=5) and fibrous plaques that contained mostly extracellular matrix without a lipid core (n=4). Strong TLR-4 expression (brown staining) was observed around the lipid core and at the shoulder of lipid-rich plaques, where it colocalized with macrophage immunoreactivity (Figure 2). Incubation of the antiserum with the peptide used to generate the primary antibody blocked TLR-4 immunoreactivity, confirming the specificity of the anti-TLR-4 antiserum. Double staining showed close spatial colocalization of TLR-4 expression with macrophage immunoreactivity (Figure 2). No TLR-4 immunoreactivity or macrophage immunoreactivity was found in fibrous plaques that demonstrated strong smooth muscle -actin immunoreactivity (Figure 2). Normal mammary arteries showed only minimal or no TLR-4 expression (Figure 2). TLR-2 immunoreactivity was absent in all plaques, whereas control staining was positive in THP-1 cells (data not shown).
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TLR-4 mRNA Regulation by Ox-LDL
Cultured human monocyte-derived macrophages were stimulated with native LDL or ox-LDL for 5 hours, RT-PCR for TLR-2 and TLR-4 was performed, and relative intensity was calculated by densitometry as described earlier.32 RT-PCR showed basal TLR-2 and TLR-4 mRNA expression by macrophages. The TLR-4 mRNA was upregulated by ox-LDL in a dose-dependent manner up to 3-fold, whereas native LDL had no effect. TLR-2 mRNA was not upregulated by ox-LDL (Figure 3).
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Discussion |
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Although precise triggers for inflammation in atherosclerosis are not fully understood, hypercholesterolemia, modified lipoproteins, and infection with organisms such as C pneumoniae and others have all been implicated. There is now evidence that C pneumoniae infection can accelerate the progression and facilitate the induction of atherosclerosis in cholesterol-fed rabbits and genetically modified atherosclerosis-prone mice.33–37 The concept of C pneumoniae-induced atherogenesis is further strengthened by the finding that antibiotic therapy against chlamydia prevents acceleration of atherosclerosis in the rabbit model.33 Ingalls et al38 have suggested LPS, and Kol et al39,40 have implicated HSP60, as the triggers for chlamydia-induced inflammatory responses. Both chlamydia infection41 and its LPS have been shown to induce foam-cell formation in monocytes.18 Persistence of LPS and/or HSP-60 in the atheroma either within intact C pneumoniae-infected cells or in the subendothelial space after cell lysis may promote atherosclerosis by continued macrophage activation. Indeed, circulating chlamydial LPS-specific immune complexes have been detected in patients with coronary heart disease.42 To date, however, the precise molecular mechanisms by which infections such as C pneumoniae contribute to the progression of atherosclerosis and the links among lipids, microbial antigens, and innate immune and inflammatory responses are not well understood.
Activation of monocytes/macrophages is an important initial step in the cascades of events leading to many inflammatory diseases, including atherosclerosis. The recent findings that TLR-4 is the signaling LPS receptor and also recognizes HSP60 provided a new impetus in elucidating the role of TLR-4 in various inflammatory diseases. Furthermore, a recent study showed that saturated fatty acids, but not unsaturated fatty acids, induce NF-B activation and expression of cyclooxygenase-2 through the TLR-4 receptor as well.43
In this study, we show for the first time that the proinflammatory signaling receptor TLR-4 is expressed in lipid-rich, macrophage-infiltrated atherosclerotic lesions of mice and humans and that TLR-4 mRNA in cultured macrophages is upregulated by ox-LDL but not native LDL. Together, these findings raise the possibility that enhanced TLR-4 expression may play a role in inflammation in atherosclerosis, supporting the emerging paradigm.1,44–46
Cells of the innate immune system, such as macrophages, have the ability to recognize common and conserved structural components of microbial origin by pattern recognition receptors. The human homologue of drosophila Toll, TLR-4, is a pattern recognition receptor that activates NF-B and upregulates a variety of inflammatory genes in response to microbial pathogens.47 TLRs play a fundamental role in the activation of innate immune responses and pathogen recognition. Activation of NF-B is essential for the regulation of a variety of genes involved in the inflammatory and proliferative responses of cells critical to atherogenesis.48,49 Both NF-B and genes regulated by NF-B are expressed in atherosclerotic lesions.49 Because NF-B activation leads to transcription of a number of proinflammatory genes involved in atherothrombosis, it is tempting to speculate that infectious agents and chlamydial antigens, such as LPS and/or HSP-60, might contribute to enhanced and chronic inflammation by signaling through the TLR-4 receptor, which is upregulated by ox-LDL.
Our findings of increased expression of TLR-4 induced by ox-LDL suggest a potential mechanism for the synergistic effects of hypercholesterolemia and infection in acceleration of atherosclerosis observed in experimental models35,36 and human epidemiological observations.50 Thus, these findings provide additional new insights into the link among lipids, infection/inflammation, and atherosclerosis.
In summary, we observed that human TLR-4 but not TLR-2 is expressed in murine and human lipid-rich atherosclerotic plaques, including areas infiltrated by macrophages. Furthermore, we show that ox-LDL but not native LDL induces upregulation of TLR-4 expression in macrophages. Given that TLR-4 plays a critical role in inflammatory and immune signaling, upregulated TLR-4 may participate in the inflammatory responses linking lipids to chronic infection, inflammation, and atherosclerosis. Improved understanding of the molecular mechanisms driving TLR-4 overexpression and signaling and the role of the resulting chronic inflammation during atherosclerosis may provide new targets for antiatherogenic therapy.
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Acknowledgments |
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This study was supported by NIH grants HL-51087 and AI-50699 to Dr Arditi.
Received September 5, 2001; revision received October 11, 2001; accepted October 11, 2001.
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 M. Westerterp, J. F.P. Berbee, N. M.M. Pires, G. J.D. van Mierlo, R. Kleemann, J. A. Romijn, L. M. Havekes, and P. C.N. Rensen Apolipoprotein C-I Is Crucially Involved in Lipopolysaccharide-Induced Atherosclerosis Development in Apolipoprotein E Knockout Mice Circulation, November 6, 2007; 116(19): 2173 - 2181. [Abstract] [Full Text] [PDF]
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M. Shinohara, K.-i. Hirata, T. Yamashita, T. Takaya, N. Sasaki, R. Shiraki, T. Ueyama, N. Emoto, N. Inoue, M. Yokoyama, et al. Local Overexpression of Toll-Like Receptors at the Vessel Wall Induces Atherosclerotic Lesion Formation: Synergism of TLR2 and TLR4 Arterioscler. Thromb. Vasc. Biol., November 1, 2007; 27(11): 2384 - 2391. [Abstract] [Full Text] [PDF]
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A. Niessner, M. S. Shin, O. Pryshchep, J. J. Goronzy, E. L. Chaikof, and C. M. Weyand Synergistic Proinflammatory Effects of the Antiviral Cytokine Interferon-{alpha} and Toll-Like Receptor 4 Ligands in the Atherosclerotic Plaque Circulation, October 30, 2007; 116(18): 2043 - 2052. [Abstract] [Full Text] [PDF]
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Shuang Chen, M. H. Wong, D. J. Schulte, M. Arditi, and K. S. Michelsen Differential expression of Toll-like receptor 2 (TLR2) and responses to TLR2 ligands between human and murine vascular endothelial cells Innate Immunity, October 1, 2007; 13(5): 281 - 296. [Abstract] [PDF]
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A. F. Pasini, M. Anselmi, U. Garbin, E. Franchi, C. Stranieri, M.C. Nava, V. Boccioletti, C. Vassanelli, and L. Cominacini Enhanced Levels of Oxidized Low-Density Lipoprotein Prime Monocytes to Cytokine Overproduction via Upregulation of CD14 and Toll-Like Receptor 4 in Unstable Angina Arterioscler. Thromb. Vasc. Biol., September 1, 2007; 27(9): 1991 - 1997. [Abstract] [Full Text] [PDF]
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P. M. Lepper, C. Schumann, K. Triantafilou, F. M. Rasche, T. Schuster, H. Frank, E. M. Schneider, M. Triantafilou, and M. von Eynatten Association of Lipopolysaccharide-Binding Protein and Coronary Artery Disease in Men J. Am. Coll. Cardiol., July 3, 2007; 50(1): 25 - 31. [Abstract] [Full Text] [PDF]
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 P. K. Shah Innate Immune Pathway Links Obesity to Insulin Resistance Circ. Res., June 8, 2007; 100(11): 1531 - 1533. [Full Text] [PDF]
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C.-P. Liang, S. Han, T. Senokuchi, and A. R. Tall The Macrophage at the Crossroads of Insulin Resistance and Atherosclerosis Circ. Res., June 8, 2007; 100(11): 1546 - 1555. [Abstract] [Full Text] [PDF]
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F. Kim, M. Pham, I. Luttrell, D. D. Bannerman, J. Tupper, J. Thaler, T. R. Hawn, E. W. Raines, and M. W. Schwartz Toll-Like Receptor-4 Mediates Vascular Inflammation and Insulin Resistance in Diet-Induced Obesity Circ. Res., June 8, 2007; 100(11): 1589 - 1596. [Abstract] [Full Text] [PDF]
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 R. Labrum, S. Bevan, M. Sitzer, M. Lorenz, and H. S. Markus Toll Receptor Polymorphisms and Carotid Artery Intima-Media Thickness Stroke, April 1, 2007; 38(4): 1179 - 1184. [Abstract] [Full Text] [PDF]
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 P.J. Ford, E. Gemmell, P. Timms, A. Chan, F.M. Preston, and G.J. Seymour Anti-P. gingivalis Response Correlates with Atherosclerosis Journal of Dental Research, January 1, 2007; 86(1): 35 - 40. [Abstract] [Full Text] [PDF]
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A. Niessner, K. Sato, E. L. Chaikof, I. Colmegna, J. J. Goronzy, and C. M. Weyand Pathogen-Sensing Plasmacytoid Dendritic Cells Stimulate Cytotoxic T-Cell Function in the Atherosclerotic Plaque Through Interferon-{alpha} Circulation, December 5, 2006; 114(23): 2482 - 2489. [Abstract] [Full Text] [PDF]
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Z.-q. Yan Regulation of TLR4 Expression Is a Tale About Tail. Arterioscler. Thromb. Vasc. Biol., December 1, 2006; 26(12): 2582 - 2584. [Full Text] [PDF]
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F.-Y. Lin, Y.-H. Chen, Y.-W. Lin, J.-S. Tsai, J.-W. Chen, H.-J. Wang, Y.-L. Chen, C.-Y. Li, and S.-J. Lin The Role of Human Antigen R, an RNA-binding Protein, in Mediating the Stabilization of Toll-Like Receptor 4 mRNA Induced by Endotoxin: A Novel Mechanism Involved in Vascular Inflammation Arterioscler. Thromb. Vasc. Biol., December 1, 2006; 26(12): 2622 - 2629. [Abstract] [Full Text] [PDF]
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F.-Y. Lin, Y.-H. Chen, J.-S. Tasi, J.-W. Chen, T.-L. Yang, H.-J. Wang, C.-Y. Li, Y.-L. Chen, and S.-J. Lin Endotoxin Induces Toll-Like Receptor 4 Expression in Vascular Smooth Muscle Cells via NADPH Oxidase Activation and Mitogen-Activated Protein Kinase Signaling Pathways Arterioscler. Thromb. Vasc. Biol., December 1, 2006; 26(12): 2630 - 2637. [Abstract] [Full Text] [PDF]
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 W. Koch, P. Hoppmann, A. Pfeufer, A. Schomig, and A. Kastrati Toll-like receptor 4 gene polymorphisms and myocardial infarction: no association in a Caucasian population Eur. Heart J., November 1, 2006; 27(21): 2524 - 2529. [Abstract] [Full Text] [PDF]
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 M. K. Mohammad, M. Morran, B. Slotterbeck, D. W. Leaman, Y. Sun, H. v. Grafenstein, S.-C. Hong, and M. F. McInerney Dysregulated Toll-like receptor expression and signaling in bone marrow-derived macrophages at the onset of diabetes in the non-obese diabetic mouse Int. Immunol., July 1, 2006; 18(7): 1101 - 1113. [Abstract] [Full Text] [PDF]
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P. Holvoet, P. C. Davey, D. De Keyzer, M. Doukoure, E. Deridder, M.-L. Bochaton-Piallat, G. Gabbiani, E. Beaufort, K. Bishay, N. Andrieux, et al. Oxidized Low-Density Lipoprotein Correlates Positively With Toll-Like Receptor 2 and Interferon Regulatory Factor-1 and Inversely With Superoxide Dismutase-1 Expression: Studies in Hypercholesterolemic Swine and THP-1 Cells Arterioscler. Thromb. Vasc. Biol., July 1, 2006; 26(7): 1558 - 1565. [Abstract] [Full Text] [PDF]
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 L. Romics Jr, G. Szabo, J. C. Coffey, J. H. Wang, and H. P. Redmond The Emerging Role of Toll-Like Receptor Pathways in Surgical Diseases Arch Surg, June 1, 2006; 141(6): 595 - 601. [Abstract] [Full Text] [PDF]
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 A. Tedgui and Z. Mallat Cytokines in Atherosclerosis: Pathogenic and Regulatory Pathways Physiol Rev, April 1, 2006; 86(2): 515 - 581. [Abstract] [Full Text] [PDF]
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 T. Miyamoto, H. Yumoto, Y. Takahashi, M. Davey, F. C. Gibson III, and C. A. Genco Pathogen-Accelerated Atherosclerosis Occurs Early after Exposure and Can Be Prevented via Immunization Infect. Immun., February 1, 2006; 74(2): 1376 - 1380. [Abstract] [Full Text] [PDF]
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F.C. Gibson III, H. Yumoto, Y. Takahashi, H.-H. Chou, and C.A. Genco Innate Immune Signaling and Porphyromonas gingivalis-accelerated Atherosclerosis Journal of Dental Research, February 1, 2006; 85(2): 106 - 121. [Abstract] [Full Text] [PDF]
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H. Yumoto, H.-H. Chou, Y. Takahashi, M. Davey, F. C. Gibson III, and C. A. Genco Sensitization of Human Aortic Endothelial Cells to Lipopolysaccharide via Regulation of Toll-Like Receptor 4 by Bacterial Fimbria-Dependent Invasion Infect. Immun., December 1, 2005; 73(12): 8050 - 8059. [Abstract] [Full Text] [PDF]
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 U. Singh, J. Tabibian, S. K. Venugopal, S. Devaraj, and I. Jialal Development of an In Vitro Screening Assay to Test the Antiinflammatory Properties of Dietary Supplements and Pharmacologic Agents Clin. Chem., December 1, 2005; 51(12): 2252 - 2256. [Abstract] [Full Text] [PDF]
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R. Virmani, F. D. Kolodgie, A. P. Burke, A. V. Finn, H. K. Gold, T. N. Tulenko, S. P. Wrenn, and J. Narula Atherosclerotic Plaque Progression and Vulnerability to Rupture: Angiogenesis as a Source of Intraplaque Hemorrhage Arterioscler. Thromb. Vasc. Biol., October 1, 2005; 25(10): 2054 - 2061. [Abstract] [Full Text] [PDF]
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 M Rattazzi, E Faggin, B Bertipaglia, and P Pauletto Innate immunity and atherogenesis Lupus, September 1, 2005; 14(9): 747 - 751. [Abstract] [PDF]
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H. Methe, J.-O. Kim, S. Kofler, M. Nabauer, and M. Weis Statins Decrease Toll-Like Receptor 4 Expression and Downstream Signaling in Human CD14+ Monocytes Arterioscler. Thromb. Vasc. Biol., July 1, 2005; 25(7): 1439 - 1445. [Abstract] [Full Text] [PDF]
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G. K. Hansson and K. Edfeldt Toll To Be Paid at the Gateway to the Vessel Wall Arterioscler. Thromb. Vasc. Biol., June 1, 2005; 25(6): 1085 - 1087. [Full Text] [PDF]
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H. Methe, J.-O. Kim, S. Kofler, M. Weis, M. Nabauer, and J. Koglin Expansion of Circulating Toll-Like Receptor 4-Positive Monocytes in Patients With Acute Coronary Syndrome Circulation, May 24, 2005; 111(20): 2654 - 2661. [Abstract] [Full Text] [PDF]
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S. Z.H. Rittersma, J. A. Kremer Hovinga, K. T. Koch, S. M. Boekholdt, B. E. van Aken, A. Scheepmaker, M. Bax, C. E. Schotborgh, J. J. Piek, J. G.P. Tijssen, et al. Relationship between In Vitro Lipopolysaccharide-Induced Cytokine Response in Whole Blood, Angiographic In-Stent Restenosis, and Toll-Like Receptor 4 Gene Polymorphisms Clin. Chem., March 1, 2005; 51(3): 516 - 521. [Abstract] [Full Text] [PDF]
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 Y. Naiki, K. S. Michelsen, W. Zhang, S. Chen, T. M. Doherty, and M. Arditi Transforming Growth Factor-{beta} Differentially Inhibits MyD88-dependent, but Not TRAM- and TRIF-dependent, Lipopolysaccharide-induced TLR4 Signaling J. Biol. Chem., February 18, 2005; 280(7): 5491 - 5495. [Abstract] [Full Text] [PDF]
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J. Nilsson, G. K. Hansson, and P. K. Shah Immunomodulation of Atherosclerosis: Implications for Vaccine Development Arterioscler. Thromb. Vasc. Biol., January 1, 2005; 25(1): 18 - 28. [Abstract] [Full Text] [PDF]
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K. S. Michelsen, T. M. Doherty, P. K. Shah, and M. Arditi Role of Toll-Like Receptors in Atherosclerosis Circ. Res., December 10, 2004; 95(12): e96 - e97. [Full Text] [PDF]
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L. L. Stoll, G. M. Denning, and N. L. Weintraub Potential Role of Endotoxin as a Proinflammatory Mediator of Atherosclerosis Arterioscler. Thromb. Vasc. Biol., December 1, 2004; 24(12): 2227 - 2236. [Abstract] [Full Text] [PDF]
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K. S. Michelsen, T. M. Doherty, P. K. Shah, and M. Arditi TLR Signaling: An Emerging Bridge from Innate Immunity to Atherogenesis J. Immunol., November 15, 2004; 173(10): 5901 - 5907. [Abstract] [Full Text] [PDF]
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R Arroyo-Espliguero, P Avanzas, S Jeffery, and J C Kaski CD14 and toll-like receptor 4: a link between infection and acute coronary events? Heart, September 1, 2004; 90(9): 983 - 988. [Abstract] [Full Text] [PDF]
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K. Edfeldt, A. M Bennet, P. Eriksson, J. Frostegard, B. Wiman, A. Hamsten, G. K Hansson, U. d. Faire, and Z.-q. Yan Association of hypo-responsive toll-like receptor 4 variants with risk of myocardial infarction Eur. Heart J., August 2, 2004; 25(16): 1447 - 1453. [Abstract] [Full Text] [PDF]
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 K. S. Michelsen, M. H. Wong, P. K. Shah, W. Zhang, J. Yano, T. M. Doherty, S. Akira, T. B. Rajavashisth, and M. Arditi Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E PNAS, July 20, 2004; 101(29): 10679 - 10684. [Abstract] [Full Text] [PDF]
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 M. H. Tan, Z. Sun, S. L. Opitz, T. E. Schmidt, J. H. Peters, and E. L. George Deletion of the alternatively spliced fibronectin EIIIA domain in mice reduces atherosclerosis Blood, July 1, 2004; 104(1): 11 - 18. [Abstract] [Full Text] [PDF]
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F. C. Gibson III, C. Hong, H.-H. Chou, H. Yumoto, J. Chen, E. Lien, J. Wong, and C. Attardo Genco Innate Immune Recognition of Invasive Bacteria Accelerates Atherosclerosis in Apolipoprotein E-Deficient Mice Circulation, June 8, 2004; 109(22): 2801 - 2806. [Abstract] [Full Text] [PDF]
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D. Recalde, M. A. Ostos, E. Badell, A.-L. Garcia-Otin, J. Pidoux, G. Castro, M. M. Zakin, and D. Scott-Algara Human Apolipoprotein A-IV Reduces Secretion of Proinflammatory Cytokines and Atherosclerotic Effects of a Chronic Infection Mimicked by Lipopolysaccharide Arterioscler. Thromb. Vasc. Biol., April 1, 2004; 24(4): 756 - 761. [Abstract] [Full Text] [PDF]
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G. Pasterkamp, Z. S. Galis, and D. P.V. de Kleijn Expansive Arterial Remodeling: Location, Location, Location Arterioscler. Thromb. Vasc. Biol., April 1, 2004; 24(4): 650 - 657. [Abstract] [Full Text] [PDF]
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J.-i. Oyama, C. Blais Jr, X. Liu, M. Pu, L. Kobzik, R. A. Kelly, and T. Bourcier Reduced Myocardial Ischemia-Reperfusion Injury in Toll-Like Receptor 4-Deficient Mice Circulation, February 17, 2004; 109(6): 784 - 789. [Abstract] [Full Text] [PDF]
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S. C.G. Hollestelle, M. R. de Vries, J. K. van Keulen, A. H. Schoneveld, A. Vink, C. F. Strijder, B. J. van Middelaar, G. Pasterkamp, P. H.A. Quax, and D. P.V. de Kleijn Toll-Like Receptor 4 Is Involved in Outward Arterial Remodeling Circulation, January 27, 2004; 109(3): 393 - 398. [Abstract] [Full Text] [PDF]
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N. Ameziane, T. Beillat, P. Verpillat, S. Chollet-Martin, M.-C. Aumont, P. Seknadji, M. Lamotte, D. Lebret, V. Ollivier, and D. de Prost Association of the Toll-Like Receptor 4 Gene Asp299Gly Polymorphism With Acute Coronary Events Arterioscler. Thromb. Vasc. Biol., December 1, 2003; 23(12): e61 - e64. [Abstract] [Full Text] [PDF]
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J. B. Rice, L. L. Stoll, W.-G. Li, G. M. Denning, J. Weydert, E. Charipar, W. E. Richenbacher, F. J. Miller Jr, and N. L. Weintraub Low-Level Endotoxin Induces Potent Inflammatory Activation of Human Blood Vessels: Inhibition by Statins Arterioscler. Thromb. Vasc. Biol., September 1, 2003; 23(9): 1576 - 1582. [Abstract] [Full Text] [PDF]
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S. M. Boekholdt, W. R.P. Agema, R. J.G. Peters, A. H. Zwinderman, E. E. van der Wall, P. H. Reitsma, J. J.P. Kastelein, and J. W. Jukema Variants of Toll-Like Receptor 4 Modify the Efficacy of Statin Therapy and the Risk of Cardiovascular Events Circulation, May 20, 2003; 107(19): 2416 - 2421. [Abstract] [Full Text] [PDF]
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Y. I. Miller, S. Viriyakosol, C. J. Binder, J. R. Feramisco, T. N. Kirkland, and J. L. Witztum Minimally Modified LDL Binds to CD14, Induces Macrophage Spreading via TLR4/MD-2, and Inhibits Phagocytosis of Apoptotic Cells J. Biol. Chem., January 10, 2003; 278(3): 1561 - 1568. [Abstract] [Full Text] [PDF]
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A. Vink, A. H. Schoneveld, J. J. van der Meer, B. J. van Middelaar, J. P.G. Sluijter, M. B. Smeets, P. H.A. Quax, S. K. Lim, C. Borst, G. Pasterkamp, et al. In Vivo Evidence for a Role of Toll-Like Receptor 4 in the Development of Intimal Lesions Circulation, October 8, 2002; 106(15): 1985 - 1990. [Abstract] [Full Text] [PDF]
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Q. Xu Role of Heat Shock Proteins in Atherosclerosis Arterioscler. Thromb. Vasc. Biol., October 1, 2002; 22(10): 1547 - 1559. [Abstract] [Full Text] [PDF]
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G. K. Hansson, P. Libby, U. Schonbeck, and Z.-Q. Yan Innate and Adaptive Immunity in the Pathogenesis of Atherosclerosis Circ. Res., August 23, 2002; 91(4): 281 - 291. [Abstract] [Full Text] [PDF]
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J. A. Vita and J. Loscalzo Shouldering the Risk Factor Burden: Infection, Atherosclerosis, and the Vascular Endothelium Circulation, July 9, 2002; 106(2): 164 - 166. [Full Text] [PDF]
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K. Edfeldt, J. Swedenborg, G. K. Hansson, and Z.-q. Yan Expression of Toll-Like Receptors in Human Atherosclerotic Lesions: A Possible Pathway for Plaque Activation Circulation, March 12, 2002; 105(10): 1158 - 1161. [Abstract] [Full Text] [PDF]
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Y. Bulut, E. Faure, L. Thomas, H. Karahashi, K. S. Michelsen, O. Equils, S. G. Morrison, R. P. Morrison, and M. Arditi Chlamydial Heat Shock Protein 60 Activates Macrophages and Endothelial Cells Through Toll-Like Receptor 4 and MD2 in a MyD88-Dependent Pathway J. Immunol., February 1, 2002; 168(3): 1435 - 1440. [Abstract] [Full Text] [PDF]
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