Circulation. 2001;104:3103-3108
doi: 10.1161/hc5001.100631
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
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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|
|
|
 |
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|
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 |
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|
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|
|
|
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|
|
|
 |
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|
|
|
|
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|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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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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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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. 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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
 |
|
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|
|
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|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|