Modulation of atherosclerosis in mice by Toll-like receptor 2.
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ABSTRACT:
SUBMITTER: Mullick AE
PROVIDER: S-EPMC1242192 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveCellular fibronectin containing extra domain A (EDA(+)-FN) is abundant in the arteries of patients with atherosclerosis. Several in vitro studies suggest that EDA(+)-FN interacts with Toll-like receptor 4 (TLR4). We tested the hypothesis that EDA(+)-FN exacerbates atherosclerosis through TLR4 in a clinically relevant model of atherosclerosis, the apolipoprotein E-deficient (Apoe(-/-)) mouse.Approach and resultsThe extent of atherosclerosis was evaluated in whole aortae and cross sections of the aortic sinus in male and female EDA(-/-)Apoe(-/-) mice (which lack EDA(+)-FN), EDA(fl/fl)Apoe(-/-) mice (which constitutively express EDA(+)-FN), and control Apoe(-/-) mice fed a high-fat Western diet for 14 weeks. Irrespective of sex, EDA(fl/fl)Apoe(-/-) mice exhibited a 2-fold increase in atherosclerotic lesions (aorta and aortic sinus) and macrophage content within plaques, whereas EDA(-/-)Apoe(-/-) mice exhibited reduced atherosclerotic lesions (P<0.05 versus Apoe(-/-), n=10-12 mice/group), although cholesterol and triglyceride levels and circulating leukocytes were similar. Genetic ablation of TLR4 partially reversed atherosclerosis exacerbation in EDA(fl/fl)Apoe(-/-) mice (P<0.05) but had no effect on atherosclerotic lesions in EDA(-/-)Apoe(-/-) mice. Purified cellular FN, which contains EDA, potentiated dose-dependent NFκB-mediated inflammation (increased phospho-NFκB p65/NFκB p65, tumor necrosis factor-α, and interleukin-1β) in bone marrow-derived macrophages from EDA(-/-)Apoe(-/-) mice but not from EDA(-/-)TLR4(-/-)Apoe(-/-) mice. Finally, using immunohistochemistry, we provide evidence for the first time that EDA(+)-FN colocalizes with macrophage TLR4 in murine aortic lesions and human coronary artery atherosclerotic plaques.ConclusionsOur findings reveal that TLR4 signaling contributes to EDA(+)-FN-mediated exacerbation of atherosclerosis. We suggest that EDA(+)-FN could be a therapeutic target in atherosclerosis.
| S-EPMC4618710 | biostudies-literature
Project description:Toll-like receptor 4 (TLR4), along with its accessory protein myeloid differentiation factor 2 (MD-2), builds a heterodimeric complex that specifically recognizes lipopolysaccharides (LPS), which are present on the cell wall of Gram-negative bacteria, activating the innate immune response. Some TLR4 modulators are undergoing preclinical and clinical evaluation for the treatment of sepsis, inflammatory diseases, cancer and rheumatoid arthritis. Since the relatively recent elucidation of the X-ray crystallographic structure of the extracellular domain of TLR4, research around this fascinating receptor has risen to a new level, and thus, new perspectives have been opened. In particular, diverse computational techniques have been applied to decipher some of the basis at the atomic level regarding the mechanism of functioning and the ligand recognition processes involving the TLR4/MD-2 system at the atomic level. This review summarizes the reported molecular modeling and computational studies that have recently provided insights into the mechanism regulating the activation/inactivation of the TLR4/MD-2 system receptor and the key interactions modulating the molecular recognition process by agonist and antagonist ligands. These studies have contributed to the design and the discovery of novel small molecules with promising activity as TLR4 modulators.
| S-EPMC6274477 | biostudies-literature
Project description:Obesity is associated with insulin resistance, chronic low-grade inflammation, and atherosclerosis. Toll-like receptor 4 (TLR4) participates in the cross talk between inflammation and insulin resistance, being activated by both lipopolysaccharide and saturated fatty acids. The present study was undertaken to determine whether TLR4 deficiency has a protective role in inflammation, insulin resistance, and atherosclerosis induced by a diabetogenic diet.TLR4 and low-density lipoprotein (LDL) receptor double knockout mice and LDL receptor-deficient mice were fed either a normal chow or a diabetogenic diet for 24 weeks. TLR4 and LDL receptor double knockout mice fed a diabetogenic diet showed improved plasma cholesterol and triglyceride levels but developed obesity, hyperinsulinemia, and glucose intolerance equivalent to obese LDL receptor-deficient mice. Adipocyte hypertrophy, macrophage accumulation, and local inflammation were not attenuated in intraabdominal adipose tissue in TLR4 and LDL receptor double knockout mice. However, TLR4 deficiency led to markedly decreased atherosclerosis in obese TLR4 and LDL receptor double knockout mice. Compensatory upregulation of TLR2 expression was observed both in obese TLR4-deficient mice and in palmitate-treated TLR4-silenced 3T3-L1 adipocytes.TLR4 deficiency decreases atherosclerosis without affecting obesity-induced inflammation and insulin resistance in LDL receptor-deficient mice. Alternative pathways may be responsible for adipose tissue macrophage infiltration and insulin resistance that occurs in obesity.
| S-EPMC3748807 | biostudies-literature
Project description:Antimicrobial peptides (AMPs) are typically thought of as molecular hole punchers that directly kill pathogens by membrane permeation. However, recent work has shown that AMPs are pleiotropic, multifunctional molecules that can strongly modulate immune responses. In this review, we provide a historical overview of the immunomodulatory properties of natural and synthetic antimicrobial peptides, with a special focus on human cathelicidin and defensins. We also summarize the various mechanisms of AMP immune modulation and outline key structural rules underlying the recently-discovered phenomenon of AMP-mediated Toll-like receptor (TLR) signaling. In particular, we describe several complementary studies demonstrating how AMPs self-assemble with nucleic acids to form nanocrystalline complexes that amplify TLR-mediated inflammation. In a broader scope, we discuss how this new conceptual framework allows for the prediction of immunomodulatory behavior in AMPs, how the discovery of hidden antimicrobial activity in known immune signaling proteins can inform these predictions, and how these findings reshape our understanding of AMPs in normal host defense and autoimmune disease.
| S-EPMC6087683 | biostudies-literature
Project description:The impact of a dual TLR7 and TLR9 antagonist on hypercholesteremia and atherosclerosis was evaluated in hyperlipidemic mice. Treatment with antagonist induced a dose dependent reduction of total cholesterol (TC) and LDL-cholesterol. Changes in Adiponectin, Leptin and free fatty acids levels were observed. Plaque formation was inhibited in ApoE-/- and LDL-R-/- mice fed high fat diet and treated with the antagonist. Hepatic and renal steatosis was reduced by the treatment. Induction of IL-10 expression was inversely correlated with TC levels. The antagonist induced decrease in hepatic IKKα protein level and enhancement of Akt and Gsk3β phosphorylation. Treatment of C57BL/6 mice caused increase in hepatic LXR, PPARγ and ABCG1 expression and in stool content of TC. Antagonist treatment resulted in altered expression of several genes and pathways related to immune system, cholesterol, fatty acid and glucose metabolism. Data obtained suggest involvement of TLR7 and TLR9 in diet induced hyperlipidemia and atherosclerosis and demonstrate therapeutic potential of TLR7/9 antagonist.
2021-11-01 | GSE28125 | GEO
Project description:ProblemPreterm premature rupture of fetal membranes (pPROM) occurs in 30-40% of spontaneous preterm births (PTB) and is associated with intra-amniotic infection and inflammation. The membranes may sense and respond to microbes via Toll-like receptors (TLRs); however, little is known about their expression and regulation in this tissue. The objective of this study was to evaluate the expression of TLRs 1-10 in fetal membranes after exposure to pathogens associated with intra-amniotic infection and PTB.Method of studyNormal human term fetal membrane explants were exposed to various bacteria. After 24 hrs, RNA was extracted and quantitative RT-PCR performed for TLRs1-10.ResultsTreatment of fetal membranes with Mycoplasma hominis increased expression of TLR4, TLR6, and TLR8 mRNA. Ureaplasma parvum upregulated TLR8 mRNA, and Porphyromonas gingivalis significantly increased fetal membrane TLR7 expression. In contrast, treatment with Gram-negative Escherichia coli (and its cell wall component lipopolysaccharide) downregulated TLR10 mRNA. No effect was detected for Ureaplasma urealyticum, Gardnerella vaginalis, or Group B Streptococcus.ConclusionThese findings demonstrate that different types of bacteria have distinct effects on fetal membrane TLR expression patterns. Moreover, these findings highlight the disparity of fetal membrane responses to infection and thus suggest heterogeneity in the mechanisms by which infection-associated pregnancy complications, such as pPROM and PTB, arise.
| S-EPMC3535068 | biostudies-literature
Project description:BackgroundToll-like receptors (TLR) of the innate immune system have been closely linked with the development of atherosclerotic lesions. TLR9 is activated by unmethylated CpG motifs within ssDNA, but also by CpG motifs in nucleic acids released during vascular apoptosis and necrosis. The role of TLR9 in vascular disease remains controversial and we sought to investigate the effects of a proinflammatory TLR9 stimulation in mice.Methods and findingsTLR9-stimulation with high dose CpG ODN at concentrations between 6.25 nM to 30 nM induced a significant proinflammatory cytokine response in mice. This was associated with impaired reendothelialization upon acute denudation of the carotid and increased numbers of circulating endothelial microparticles, as a marker for amplified endothelial damage. Chronic TLR9 agonism in apolipoprotein E-deficient (ApoE-/-) mice fed a cholesterol-rich diet increased aortic production of reactive oxygen species, the number of circulating endothelial microparticles, circulating sca-1/flk-1 positive cells, and most importantly augmented atherosclerotic plaque formation when compared to vehicle treated animals. Importantly, high concentrations of CpG ODN are required for these proatherogenic effects.ConclusionsSystemic stimulation of TLR9 with high dose CpG ODN impaired reendothelialization upon acute vascular injury and increased atherosclerotic plaque development in ApoE-/- mice. Further studies are necessary to fully decipher the contradictory finding of TLR9 agonism in vascular biology.
| S-EPMC4709087 | biostudies-literature
Project description:BackgroundAccumulating 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.Methods and resultsTo 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.ConclusionGenetic 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.
| S-EPMC2527517 | biostudies-literature
Project description:Background Toll-like receptor ( TLR ) 9 recognizes bacterial DNA , activating innate immunity, whereas it also provokes inflammation in response to fragmented DNA released from mammalian cells. We investigated whether TLR 9 contributes to the development of vascular inflammation and atherogenesis using apolipoprotein E-deficient ( Apoe -/-) mice. Methods and Results Tlr9-deficient Apoe -/- ( Tlr9 -/- Apoe -/-) mice and Apoe -/- mice on a Western-type diet received subcutaneous angiotensin II infusion (1000 ng/kg per minute) for 28 days. Angiotensin II increased the plasma level of double-stranded DNA, an endogenous ligand of TLR 9, in these mice. Genetic deletion or pharmacologic blockade of TLR 9 in angiotensin II-infused Apoe -/- mice attenuated atherogenesis in the aortic arch ( P<0.05), reduced the accumulation of lipid and macrophages in atherosclerotic plaques, and decreased RNA expression of inflammatory molecules in the aorta with no alteration of metabolic parameters. On the other hand, restoration of TLR 9 in bone marrow in Tlr9 -/- Apoe -/- mice promoted atherogenesis in the aortic arch ( P<0.05). A TLR 9 agonist markedly promoted proinflammatory activation of Apoe -/- macrophages, partially through p38 mitogen-activated protein kinase signaling. In addition, genomic DNA extracted from macrophages promoted inflammatory molecule expression more effectively in Apoe -/- macrophages than in Tlr9 -/- Apoe -/- macrophages. Furthermore, in humans, circulating double-stranded DNA in the coronary artery positively correlated with inflammatory features of coronary plaques determined by optical coherence tomography in patients with acute myocardial infarction ( P<0.05). Conclusions TLR 9 plays a pivotal role in the development of vascular inflammation and atherogenesis through proinflammatory activation of macrophages. TLR 9 may serve as a potential therapeutic target for atherosclerosis.
| S-EPMC6509720 | biostudies-literature
Project description:Although vitamin D has been implicated in cardiovascular protection, few studies have addressed the role of vitamin D receptor (VDR) in atherosclerosis. Here we investigate the effect of inactivation of the VDR signaling on atherogenesis and the antiatherosclerotic mechanism of vitamin D. Low density lipoprotein receptor (LDLR)(-/-)/VDR(-/-) mice exhibited site-specific accelerated atherogenesis, accompanied by increases in adhesion molecules and proinflammatory cytokines in the aorta and cholesterol influx in macrophages. Macrophages showed marked renin up-regulation in the absence of VDR, and inhibition of renin by aliskiren reduced atherosclerosis in LDLR(-/-)/VDR(-/-) mice, suggesting that the renin-angiotensin system (RAS) promotes atherosclerosis in the absence of VDR. LDLR(-/-) mice receiving LDLR(-/-)/VDR(-/-) BMT developed larger lesions than LDLR(-/-) BMT controls. Moreover, LDLR(-/-) mice receiving Rag-1(-/-)/VDR(-/-) BMT, which were unable to generate functional T and B lymphocytes, still had more severe atherosclerosis than Rag-1(-/-) BMT controls, suggesting a critical role of macrophage VDR signaling in atherosclerotic suppression. Aliskiren treatment eliminated the difference in lesions between Rag-1(-/-)/VDR(-/-) BMT and Rag-1(-/-) BMT recipients, indicating that local RAS activation in macrophages contributes to the enhanced atherogenesis seen in Rag-1(-/-)/VDR(-/-) BMT mice. Taken together, these observations provide evidence that macrophage VDR signaling, in part by suppressing the local RAS, inhibits atherosclerosis in mice.
| S-EPMC3385794 | biostudies-other