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CD36/SR-B2-TLR2 Dependent Pathways Enhance Porphyromonas gingivalis Mediated Atherosclerosis in the Ldlr KO Mouse Model.

Brown PM, Kennedy DJ, Morton RE, Febbraio M - PLoS ONE (2015)

Bottom Line: Western diet feeding promoted enhanced CD36/SR-B2-dependent IL1β generation and foam cell formation as a result of Pg lipopolysaccharide (PgLPS) exposure.CD36/SR-B2 and TLR2 were necessary for inflammasome activation and optimal IL1ß generation, but also resulted in LPS induced lethality (pyroptosis).Our data show that Pg infection in the oral cavity can lead to significant TLR2-CD36/SR-B2 dependent IL1ß release.

View Article: PubMed Central - PubMed

Affiliation: Pediatric Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.

ABSTRACT
There is strong epidemiological association between periodontal disease and cardiovascular disease but underlying mechanisms remain ill-defined. Because the human periodontal disease pathogen, Porphyromonas gingivalis (Pg), interacts with innate immune receptors Toll-like Receptor (TLR) 2 and CD36/scavenger receptor-B2 (SR-B2), we studied how CD36/SR-B2 and TLR pathways promote Pg-mediated atherosclerosis. Western diet fed low density lipoprotein receptor knockout (Ldlr°) mice infected orally with Pg had a significant increase in lesion burden compared with uninfected controls.This increase was entirely CD36/SR-B2-dependent, as there was no significant change in lesion burden between infected and uninfected Cd36o/Ldlro mice [corrected]. Western diet feeding promoted enhanced CD36/SR-B2-dependent IL1β generation and foam cell formation as a result of Pg lipopolysaccharide (PgLPS) exposure. CD36/SR-B2 and TLR2 were necessary for inflammasome activation and optimal IL1ß generation, but also resulted in LPS induced lethality (pyroptosis). Modified forms of LDL inhibited Pg-mediated IL1ß generation in a CD36/SR-B2-dependent manner and prevented pyroptosis, but promoted foam cell formation. Our data show that Pg infection in the oral cavity can lead to significant TLR2-CD36/SR-B2 dependent IL1ß release. In the vessel wall, macrophages encountering systemic release of IL1ß, PgLPS and modified LDL have increased lipid uptake, foam cell formation, and release of IL1ß, but because pyroptosis is inhibited, this enables macrophage survival and promotes increased plaque development. These studies may explain increased lesion burden as a result of periodontal disease, and suggest strategies for development of therapeutics.

No MeSH data available.


Related in: MedlinePlus

Western diet feeding influences responses to Pg.A. Macrophages from WT Western diet fed (WD) mice generate higher levels of IL1β in response to PgLPS compared with macrophages from normal chow (NC) fed WT mice and macrophages from WD or NC fed Cd36° mice. One way ANOVA, p< 0.0001. Bonferroni’s Multiple Comparison Test, *p<0.05 vs all other groups. Experiment was performed in triplet and repeated once. B. PgLPS+oxLDL lead to greater lipid accumulation and foam cell formation in macrophages from Western diet fed Ldlr° mice compared with macrophages from normal chow fed mice. Experiment was performed in triplet and repeated once. Student’s t-test, *p<0.0001.
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pone.0125126.g009: Western diet feeding influences responses to Pg.A. Macrophages from WT Western diet fed (WD) mice generate higher levels of IL1β in response to PgLPS compared with macrophages from normal chow (NC) fed WT mice and macrophages from WD or NC fed Cd36° mice. One way ANOVA, p< 0.0001. Bonferroni’s Multiple Comparison Test, *p<0.05 vs all other groups. Experiment was performed in triplet and repeated once. B. PgLPS+oxLDL lead to greater lipid accumulation and foam cell formation in macrophages from Western diet fed Ldlr° mice compared with macrophages from normal chow fed mice. Experiment was performed in triplet and repeated once. Student’s t-test, *p<0.0001.

Mentions: PgLPS is a TLR ligand and CD36/SR-B2 has been shown to interact with TLRs, thus we tested the hypothesis that CD36/SR-B2 was involved in IL1β activation in response to PgLPS as a potential downstream effect of TLR signaling [55]. As shown in Fig 8C, absence of CD36/SR-B2 resulted in a significant decrease in IL1β generation by macrophages. We next investigated the effect of a high fat diet on responses to PgLPS. Isolated macrophages from WT mice fed the WD for 6 weeks showed significantly increased generation of IL1β compared with macrophages from normal chow (NC) fed mice and Cd36° mice fed either diet (Fig 9A). When incubated with oxLDL in the presence or absence of PgLPS, macrophages from WD fed Ldlr° mice showed increased foam cell formation (Fig 9B).


CD36/SR-B2-TLR2 Dependent Pathways Enhance Porphyromonas gingivalis Mediated Atherosclerosis in the Ldlr KO Mouse Model.

Brown PM, Kennedy DJ, Morton RE, Febbraio M - PLoS ONE (2015)

Western diet feeding influences responses to Pg.A. Macrophages from WT Western diet fed (WD) mice generate higher levels of IL1β in response to PgLPS compared with macrophages from normal chow (NC) fed WT mice and macrophages from WD or NC fed Cd36° mice. One way ANOVA, p< 0.0001. Bonferroni’s Multiple Comparison Test, *p<0.05 vs all other groups. Experiment was performed in triplet and repeated once. B. PgLPS+oxLDL lead to greater lipid accumulation and foam cell formation in macrophages from Western diet fed Ldlr° mice compared with macrophages from normal chow fed mice. Experiment was performed in triplet and repeated once. Student’s t-test, *p<0.0001.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4418723&req=5

pone.0125126.g009: Western diet feeding influences responses to Pg.A. Macrophages from WT Western diet fed (WD) mice generate higher levels of IL1β in response to PgLPS compared with macrophages from normal chow (NC) fed WT mice and macrophages from WD or NC fed Cd36° mice. One way ANOVA, p< 0.0001. Bonferroni’s Multiple Comparison Test, *p<0.05 vs all other groups. Experiment was performed in triplet and repeated once. B. PgLPS+oxLDL lead to greater lipid accumulation and foam cell formation in macrophages from Western diet fed Ldlr° mice compared with macrophages from normal chow fed mice. Experiment was performed in triplet and repeated once. Student’s t-test, *p<0.0001.
Mentions: PgLPS is a TLR ligand and CD36/SR-B2 has been shown to interact with TLRs, thus we tested the hypothesis that CD36/SR-B2 was involved in IL1β activation in response to PgLPS as a potential downstream effect of TLR signaling [55]. As shown in Fig 8C, absence of CD36/SR-B2 resulted in a significant decrease in IL1β generation by macrophages. We next investigated the effect of a high fat diet on responses to PgLPS. Isolated macrophages from WT mice fed the WD for 6 weeks showed significantly increased generation of IL1β compared with macrophages from normal chow (NC) fed mice and Cd36° mice fed either diet (Fig 9A). When incubated with oxLDL in the presence or absence of PgLPS, macrophages from WD fed Ldlr° mice showed increased foam cell formation (Fig 9B).

Bottom Line: Western diet feeding promoted enhanced CD36/SR-B2-dependent IL1β generation and foam cell formation as a result of Pg lipopolysaccharide (PgLPS) exposure.CD36/SR-B2 and TLR2 were necessary for inflammasome activation and optimal IL1ß generation, but also resulted in LPS induced lethality (pyroptosis).Our data show that Pg infection in the oral cavity can lead to significant TLR2-CD36/SR-B2 dependent IL1ß release.

View Article: PubMed Central - PubMed

Affiliation: Pediatric Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.

ABSTRACT
There is strong epidemiological association between periodontal disease and cardiovascular disease but underlying mechanisms remain ill-defined. Because the human periodontal disease pathogen, Porphyromonas gingivalis (Pg), interacts with innate immune receptors Toll-like Receptor (TLR) 2 and CD36/scavenger receptor-B2 (SR-B2), we studied how CD36/SR-B2 and TLR pathways promote Pg-mediated atherosclerosis. Western diet fed low density lipoprotein receptor knockout (Ldlr°) mice infected orally with Pg had a significant increase in lesion burden compared with uninfected controls.This increase was entirely CD36/SR-B2-dependent, as there was no significant change in lesion burden between infected and uninfected Cd36o/Ldlro mice [corrected]. Western diet feeding promoted enhanced CD36/SR-B2-dependent IL1β generation and foam cell formation as a result of Pg lipopolysaccharide (PgLPS) exposure. CD36/SR-B2 and TLR2 were necessary for inflammasome activation and optimal IL1ß generation, but also resulted in LPS induced lethality (pyroptosis). Modified forms of LDL inhibited Pg-mediated IL1ß generation in a CD36/SR-B2-dependent manner and prevented pyroptosis, but promoted foam cell formation. Our data show that Pg infection in the oral cavity can lead to significant TLR2-CD36/SR-B2 dependent IL1ß release. In the vessel wall, macrophages encountering systemic release of IL1ß, PgLPS and modified LDL have increased lipid uptake, foam cell formation, and release of IL1ß, but because pyroptosis is inhibited, this enables macrophage survival and promotes increased plaque development. These studies may explain increased lesion burden as a result of periodontal disease, and suggest strategies for development of therapeutics.

No MeSH data available.


Related in: MedlinePlus