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Toll-like receptor 2 plays a critical role in the progression of atherosclerosis that is independent of dietary lipids.

ABSTRACT: OBJECTIVE:Toll-like receptors (TLRs), a group of pathogen-associated microbial pattern recognition receptors, play an important role in innate immune signaling and are differentially regulated in chronic inflammatory diseases such as atherosclerosis. However, the involvement of TLRs in the progression of atherosclerosis is still unclear. METHODS AND RESULTS:TLR2 and apolipoprotein E double knockout (Tlr2(-/-)Apoe(-/-)) mice were generated and the progressive formation of atherosclerotic plaque in the aortas was examined in mice fed a normal chow diet. We demonstrate that inactivation of TLR2 resulted in reduced progression of atherosclerosis in both male and female Apoe(-/-) mice. Likewise, TLR2 deficiency resulted in a reduction in lipid accumulation and decreased macrophage recruitment to the aortic sinus, as well as reduced monocyte chemoattractant protein-1 (MCP-1) levels. Furthermore, macrophages isolated from Tlr2(-/-)Apoe(-/-) mice demonstrated significantly reduced MCP-1 production upon stimulation with a TLR2 ligand. However, no differences in acetylated low-density lipoprotein uptake and foam cell formation were observed in macrophages isolated from Tlr2(-/-)Apoe(-/-) mice as compared to Apoe(-/-) mice. CONCLUSIONS:TLR2 plays a critical role in the progression of atherosclerosis in Apoe(-/-) mice, which is independent of dietary lipids and macrophage lipid uptake.

SUBMITTER: Liu X

PROVIDER: S-EPMC2243224 | biostudies-literature | 2008 Jan

REPOSITORIES: biostudies-literature

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Toll-like receptor 2 plays a critical role in the progression of atherosclerosis that is independent of dietary lipids.

Liu Xinyan X Ukai Takashi T Yumoto Hiromichi H Davey Michael M Goswami Sulip S Gibson Frank C FC Genco Caroline A CA

Atherosclerosis 20070426 1

<h4>Objective</h4>Toll-like receptors (TLRs), a group of pathogen-associated microbial pattern recognition receptors, play an important role in innate immune signaling and are differentially regulated in chronic inflammatory diseases such as atherosclerosis. However, the involvement of TLRs in the progression of atherosclerosis is still unclear.<h4>Methods and results</h4>TLR2 and apolipoprotein E double knockout (Tlr2(-/-)Apoe(-/-)) mice were generated and the progressive formation of atheroscl ...[more]

PMID: 17466307

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Project description:Mounting evidence in humans supports an etiological role for the microbiota in inflammatory atherosclerosis. Atherosclerosis is a progressive disease characterized by accumulation of inflammatory cells and lipids in vascular tissue. While retention of lipoprotein into the sub-endothelial vascular layer is believed to be the initiating stimulus leading to the development of atherosclerosis, activation of multiple pathways related to vascular inflammation and endothelial dysfunction sustain the process by stimulating recruitment of leukocytes and immune cells into the sub-endothelial layer. The Gram-negative oral pathogen Porphyromonas gingivalis has been associated with the development and acceleration of atherosclerosis in humans and these observations have been validated in animal models. It has been proposed that common mechanisms of immune signaling link stimulation by lipids and pathogens to vascular inflammation. Despite the common outcome of P. gingivalis and lipid feeding on atherosclerosis progression, we established that these pro-atherogenic stimuli induced distinct gene signatures in the ApoE-/- mouse model of atherosclerosis. In this study, we further defined the distinct roles of dietary lipids and P. gingivalis infection on atherosclerosis progression and the gut microbiota. We demonstrate that diet-induced lipid lowering resulted in less atherosclerotic plaque in ApoE-/- mice compared to ApoE-/- mice continuously fed a Western diet. However, the effect of diet-induced lipid lowering on plaque accumulation was blunted by P. gingivalis infection. Using principal component analysis and hierarchical clustering, we demonstrate that dietary intervention as well as P. gingivalis infection result in distinct bacterial communities in fecal and cecal samples of ApoE-/- mice as compared to ApoE-/- mice continuously fed either a Western diet or a normal chow diet. Collectively, we identified distinct microbiota changes accompanying atherosclerotic plaque, suggesting a future avenue for investigation on the impact of the gut microbiota, diet, and P. gingivalis infection on atherosclerosis.

Project description:UnlabelledThe Toll-like receptor 4 (TLR4) that recognizes endotoxin, a trigger of inflammation in alcoholic liver disease (ALD), activates two signaling pathways utilizing different adapter molecules: the common TLR adapter, myeloid differentiation factor 88 (MyD88), or Toll/interleukin immune-response-domain-containing adaptor inducing interferon (IFN)-beta. The MyD88 pathway induces proinflammatory cytokine activation, a critical mediator of ALD. Here we evaluated the role of MyD88 in alcohol-induced liver injury in wild-type, TLR2-deficient, TLR4-deficient, or MyD88-deficient (knockout [KO]) mice after administration of the Lieber-De-Carli diet (4.5% volume/volume ethanol) or an isocaloric liquid control diet for 5 weeks. Alcohol feeding resulted in a significant increase in serum alanine aminotransferase levels, liver steatosis and triglyceride levels suggesting liver damage in WT, TLR2-KO, and MyD88-KO but not in TLR4-KO mice. Expression of inflammatory mediators (tumor necrosis factor-alpha and interleukin-6) and TLR4 coreceptors (CD14 and MD2) was significantly higher in livers of alcohol-fed WT, TLR2-KO, or MyD88-KO, but not in TLR4-KO mice, compared to controls. Reactive oxygen radicals produced by cytochrome P450 and the nicotinamide adenine dinucleotide phosphate complexes contribute to alcoholic liver damage. Alcohol feeding-induced expression and activation of cytochrome P450 and the nicotinamide adenine dinucleotide phosphate complex were prevented by TLR4-deficiency but not by MyD88-deficiency. Liver expression of interferon regulatory factor 3 (IRF3), a MyD88-independent signaling molecule, was not affected by chronic alcohol treatment in whole livers of WT mice or in any of the KO mice. However, the induction of IRF7, an IRF3-inducible gene, was found in Kupffer cells of alcohol-fed WT mice. Alcohol feeding also induced nuclear factor-kappaB activation in a TLR4-dependent MyD88-independent manner.ConclusionWhile TLR4 deficiency was protective, MyD88 deficiency failed to prevent alcohol-induced liver damage and inflammation. These results suggest that the common TLR adapter, MyD88, is dispensable in TLR4-mediated liver injury in ALD.

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Toll-like receptor 2 plays a critical role in the progression of atherosclerosis that is independent of dietary lipids.

Publications

Toll-like receptor 2 plays a critical role in the progression of atherosclerosis that is independent of dietary lipids.

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