Toll-like receptor-2 mediates diet and/or pathogen associated atherosclerosis: proteomic findings.
Accumulating evidence implicates a fundamental link between the immune system and atherosclerosis. Toll-like receptors are principal sensors of the innate immune system. Here we report an assessment of the role of the TLR2 pathway in atherosclerosis associated with a high-fat diet and/or bacteria in...
| Main Authors: | , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2008-09-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC2527517?pdf=render |
| _version_ | 1819092195285663744 |
|---|---|
| author | Monika Madan Salomon Amar |
| author_facet | Monika Madan Salomon Amar |
| author_sort | Monika Madan |
| collection | DOAJ |
| description | Accumulating evidence implicates a fundamental link between the immune system and atherosclerosis. Toll-like receptors are principal sensors of the innate immune system. Here we report an assessment of the role of the TLR2 pathway in atherosclerosis associated with a high-fat diet and/or bacteria in ApoE(+/-) mice.To explore the role of TLR2 in inflammation- and infection-associated atherosclerosis, 10 week-old ApoE(+/-)-TLR2(+/+), ApoE(+/-)-TLR2(+/-) and ApoE(+/-)-TLR2(-/-) mice were fed either a high fat diet or a regular chow diet. All mice were inoculated intravenously, once per week for 24 consecutive weeks, with 50 microl live Porphyromonas gingivalis (P.g) (10(7) CFU) or vehicle (normal saline). Animals were euthanized 24 weeks after the first inoculation. ApoE(+/-)-TLR2(+/+) mice showed a significant increase in atheromatous lesions in proximal aorta and aortic tree compared to ApoE(+/-)-TLR2(+/-) and ApoE(+/-)-TLR2(-/-) mice for all diet conditions. They also displayed profound changes in plaque composition, as evidenced by increased macrophage infiltration and apoptosis, increased lipid content, and decreased smooth muscle cell mass, all reflecting an unstable plaque phenotype. SAA levels from ApoE(+/-)-TLR2(+/+) mice were significantly higher than from ApoE(+/-)-TLR2(+/-) and ApoE(+/-)-TLR2(-/-) mice. Serum cytokine analysis revealed increased levels of pro-inflammatory cytokines in ApoE(+/-)-TLR2(+/+) mice compared to ApoE(+/-)-TLR2(+/-) and TLR2(-/-) mice, irrespective of diet or bacterial challenge. ApoE(+/-)-TLR2(+/+) mice injected weekly for 24 weeks with FSL-1 (a TLR2 agonist) also demonstrated significant increases in atherosclerotic lesions, SAA and serum cytokine levels compared to ApoE(+/-)-TLR2(-/-) mice under same treatment condition. Finally, mass-spectrometry (MALDI-TOF-MS) of aortic samples analyzed by 2-dimensional gel electrophoresis differential display, identified 6 proteins upregulated greater than 2-fold in ApoE(+/-)-TLR2(+/+) mice fed the high fat diet and inoculated with P.g compared to any other group.Genetic deficiency of TLR2 reduces diet- and/or pathogen-associated atherosclerosis in ApoE(+/-) mice, along with differences in plaque composition suggesting greater structural stability while TLR-2 ligand-specific activation triggers atherosclerosis. The present data offers new insights into the pathophysiological pathways involved in atherosclerosis and paves the way for new pharmacological interventions aimed at reducing atherosclerosis. |
| first_indexed | 2024-12-21T22:51:45Z |
| format | Article |
| id | doaj.art-9a4381650c8342fd93ebcea816f7704d |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-21T22:51:45Z |
| publishDate | 2008-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-9a4381650c8342fd93ebcea816f7704d2022-12-21T18:47:34ZengPublic Library of Science (PLoS)PLoS ONE1932-62032008-09-0139e320410.1371/journal.pone.0003204Toll-like receptor-2 mediates diet and/or pathogen associated atherosclerosis: proteomic findings.Monika MadanSalomon AmarAccumulating evidence implicates a fundamental link between the immune system and atherosclerosis. Toll-like receptors are principal sensors of the innate immune system. Here we report an assessment of the role of the TLR2 pathway in atherosclerosis associated with a high-fat diet and/or bacteria in ApoE(+/-) mice.To explore the role of TLR2 in inflammation- and infection-associated atherosclerosis, 10 week-old ApoE(+/-)-TLR2(+/+), ApoE(+/-)-TLR2(+/-) and ApoE(+/-)-TLR2(-/-) mice were fed either a high fat diet or a regular chow diet. All mice were inoculated intravenously, once per week for 24 consecutive weeks, with 50 microl live Porphyromonas gingivalis (P.g) (10(7) CFU) or vehicle (normal saline). Animals were euthanized 24 weeks after the first inoculation. ApoE(+/-)-TLR2(+/+) mice showed a significant increase in atheromatous lesions in proximal aorta and aortic tree compared to ApoE(+/-)-TLR2(+/-) and ApoE(+/-)-TLR2(-/-) mice for all diet conditions. They also displayed profound changes in plaque composition, as evidenced by increased macrophage infiltration and apoptosis, increased lipid content, and decreased smooth muscle cell mass, all reflecting an unstable plaque phenotype. SAA levels from ApoE(+/-)-TLR2(+/+) mice were significantly higher than from ApoE(+/-)-TLR2(+/-) and ApoE(+/-)-TLR2(-/-) mice. Serum cytokine analysis revealed increased levels of pro-inflammatory cytokines in ApoE(+/-)-TLR2(+/+) mice compared to ApoE(+/-)-TLR2(+/-) and TLR2(-/-) mice, irrespective of diet or bacterial challenge. ApoE(+/-)-TLR2(+/+) mice injected weekly for 24 weeks with FSL-1 (a TLR2 agonist) also demonstrated significant increases in atherosclerotic lesions, SAA and serum cytokine levels compared to ApoE(+/-)-TLR2(-/-) mice under same treatment condition. Finally, mass-spectrometry (MALDI-TOF-MS) of aortic samples analyzed by 2-dimensional gel electrophoresis differential display, identified 6 proteins upregulated greater than 2-fold in ApoE(+/-)-TLR2(+/+) mice fed the high fat diet and inoculated with P.g compared to any other group.Genetic deficiency of TLR2 reduces diet- and/or pathogen-associated atherosclerosis in ApoE(+/-) mice, along with differences in plaque composition suggesting greater structural stability while TLR-2 ligand-specific activation triggers atherosclerosis. The present data offers new insights into the pathophysiological pathways involved in atherosclerosis and paves the way for new pharmacological interventions aimed at reducing atherosclerosis.http://europepmc.org/articles/PMC2527517?pdf=render |
| spellingShingle | Monika Madan Salomon Amar Toll-like receptor-2 mediates diet and/or pathogen associated atherosclerosis: proteomic findings. PLoS ONE |
| title | Toll-like receptor-2 mediates diet and/or pathogen associated atherosclerosis: proteomic findings. |
| title_full | Toll-like receptor-2 mediates diet and/or pathogen associated atherosclerosis: proteomic findings. |
| title_fullStr | Toll-like receptor-2 mediates diet and/or pathogen associated atherosclerosis: proteomic findings. |
| title_full_unstemmed | Toll-like receptor-2 mediates diet and/or pathogen associated atherosclerosis: proteomic findings. |
| title_short | Toll-like receptor-2 mediates diet and/or pathogen associated atherosclerosis: proteomic findings. |
| title_sort | toll like receptor 2 mediates diet and or pathogen associated atherosclerosis proteomic findings |
| url | http://europepmc.org/articles/PMC2527517?pdf=render |
| work_keys_str_mv | AT monikamadan tolllikereceptor2mediatesdietandorpathogenassociatedatherosclerosisproteomicfindings AT salomonamar tolllikereceptor2mediatesdietandorpathogenassociatedatherosclerosisproteomicfindings |