Toll-like receptor-2 mediates inflammation and matrix degradation in human atherosclerosis.
BACKGROUND: Inflammation and matrix degradation are the hallmarks of high-risk atherosclerosis that leads to myocardial infarction and stroke. Toll-like receptors (TLRs), key players in innate immunity, are upregulated in atherosclerotic lesions, but their functional role in human atherosclerosis i...
| Main Authors: | , , , , , |
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| Format: | Journal article |
| Language: | English |
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2009
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| _version_ | 1797081458359140352 |
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| author | Monaco, C Gregan, S Navin, T Foxwell, B Davies, A Feldmann, M |
| author_facet | Monaco, C Gregan, S Navin, T Foxwell, B Davies, A Feldmann, M |
| author_sort | Monaco, C |
| collection | OXFORD |
| description | BACKGROUND: Inflammation and matrix degradation are the hallmarks of high-risk atherosclerosis that leads to myocardial infarction and stroke. Toll-like receptors (TLRs), key players in innate immunity, are upregulated in atherosclerotic lesions, but their functional role in human atherosclerosis is unknown. We explored the effects of blocking TLR-2, TLR-4, and myeloid differentiation primary response gene 88 (MyD88), a signaling adaptor shared by most TLRs and interleukin-1 receptor (IL-1R), in an in vitro model of human atherosclerosis. METHODS AND RESULTS: Carotid endarterectomies were obtained from patients with symptomatic carotid disease. Cells were isolated via enzymatic tissue dissociation and cultured in the presence or absence of TLR signaling blockers. A dominant-negative form of MyD88 (MyD88(DN)) decreased the production of monocyte chemotactic protein-1/CCL2 (P=0.000), IL-8/CXCL8 (P=0.006), IL-6 (P=0.002), matrix metalloproteinase-1 (MMP-1; P=0.002), and MMP-3 (P=0.000), as well as nuclear factor-kappaB activation (P<0.05) in atheroma cell cultures. IL-1R antagonist, TLR-4 blocking antibodies, or overexpression of a dominant-negative form of the TLR-4 signaling adaptor TRIF-related adaptor molecule reduced nuclear factor-kappaB activity but did not have a broad impact on the production of the mediators studied. In contrast, TLR-2 neutralizing antibodies inhibited nuclear factor-kappaB activation (P<0.05) and significantly reduced monocyte chemotactic protein-1/CCL2 (P=0.000), IL-8/CXCL8 (P=0.009), IL-6 (P=0.000), and MMP-1 (P=0.000), MMP-2 (P=0.004), MMP-3 (P=0.000), and MMP-9 (P=0.006) production. CONCLUSIONS: Our data indicate that TLR-2 signaling through MyD88 plays a predominant role in inflammation and matrix degradation in human atherosclerosis. TLR-2 blockade may represent a therapeutic strategy for atherosclerosis and its complications. |
| first_indexed | 2024-03-07T01:14:38Z |
| format | Journal article |
| id | oxford-uuid:8e3b86cb-ec0e-4a0a-9ec2-59cf4d43538f |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T01:14:38Z |
| publishDate | 2009 |
| record_format | dspace |
| spelling | oxford-uuid:8e3b86cb-ec0e-4a0a-9ec2-59cf4d43538f2022-03-26T22:56:16ZToll-like receptor-2 mediates inflammation and matrix degradation in human atherosclerosis.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:8e3b86cb-ec0e-4a0a-9ec2-59cf4d43538fEnglishSymplectic Elements at Oxford2009Monaco, CGregan, SNavin, TFoxwell, BDavies, AFeldmann, M BACKGROUND: Inflammation and matrix degradation are the hallmarks of high-risk atherosclerosis that leads to myocardial infarction and stroke. Toll-like receptors (TLRs), key players in innate immunity, are upregulated in atherosclerotic lesions, but their functional role in human atherosclerosis is unknown. We explored the effects of blocking TLR-2, TLR-4, and myeloid differentiation primary response gene 88 (MyD88), a signaling adaptor shared by most TLRs and interleukin-1 receptor (IL-1R), in an in vitro model of human atherosclerosis. METHODS AND RESULTS: Carotid endarterectomies were obtained from patients with symptomatic carotid disease. Cells were isolated via enzymatic tissue dissociation and cultured in the presence or absence of TLR signaling blockers. A dominant-negative form of MyD88 (MyD88(DN)) decreased the production of monocyte chemotactic protein-1/CCL2 (P=0.000), IL-8/CXCL8 (P=0.006), IL-6 (P=0.002), matrix metalloproteinase-1 (MMP-1; P=0.002), and MMP-3 (P=0.000), as well as nuclear factor-kappaB activation (P<0.05) in atheroma cell cultures. IL-1R antagonist, TLR-4 blocking antibodies, or overexpression of a dominant-negative form of the TLR-4 signaling adaptor TRIF-related adaptor molecule reduced nuclear factor-kappaB activity but did not have a broad impact on the production of the mediators studied. In contrast, TLR-2 neutralizing antibodies inhibited nuclear factor-kappaB activation (P<0.05) and significantly reduced monocyte chemotactic protein-1/CCL2 (P=0.000), IL-8/CXCL8 (P=0.009), IL-6 (P=0.000), and MMP-1 (P=0.000), MMP-2 (P=0.004), MMP-3 (P=0.000), and MMP-9 (P=0.006) production. CONCLUSIONS: Our data indicate that TLR-2 signaling through MyD88 plays a predominant role in inflammation and matrix degradation in human atherosclerosis. TLR-2 blockade may represent a therapeutic strategy for atherosclerosis and its complications. |
| spellingShingle | Monaco, C Gregan, S Navin, T Foxwell, B Davies, A Feldmann, M Toll-like receptor-2 mediates inflammation and matrix degradation in human atherosclerosis. |
| title | Toll-like receptor-2 mediates inflammation and matrix degradation in human atherosclerosis. |
| title_full | Toll-like receptor-2 mediates inflammation and matrix degradation in human atherosclerosis. |
| title_fullStr | Toll-like receptor-2 mediates inflammation and matrix degradation in human atherosclerosis. |
| title_full_unstemmed | Toll-like receptor-2 mediates inflammation and matrix degradation in human atherosclerosis. |
| title_short | Toll-like receptor-2 mediates inflammation and matrix degradation in human atherosclerosis. |
| title_sort | toll like receptor 2 mediates inflammation and matrix degradation in human atherosclerosis |
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