Infection and atherosclerosis: TLR-dependent pathways

Li, Bowei; Xia, Yuanpeng; Hu, Bo

doi:10.1007/s00018-020-03453-7

Cited by 110 publications

(86 citation statements)

References 182 publications

(182 reference statements)

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“…These innate immune responses are commonly activated in innate immune cells. Likewise, as a chronic in ammation process, atherosclerosis was closely bound with the continuous innate immune response triggered by activation of PPRs [24]. Basically, oxLDL is a principle component of endogenous lipid ligand that causes endothelial cell injury, accumulates in macrophage and VSMCs and induces a cellular in ammation response [25,26].…”

Section: Discussionmentioning

confidence: 99%

Toll-Like Receptor 4 Mediated Oxidized Low-Density Lipoprotein-Induced Foam Cell Formation in Vascular Smooth Muscle Cells

Chen

Xue

Cao

et al. 2020

Preprint

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Background: Oxidized low-density lipoprotein (oxLDL) induced a foam-cell like phenotype of the vascular smooth muscle cells (VSMCs), leading to the inflammatory responses incorporating Toll-like receptors (Tlrs)-mediated cellular alterations. We previously found that Tlr4 participated in inflammation response in VSMCs under oxLDL stimulation. However, the role of Tlr4 in foam-cell formation and underlying molecular pathways has not been comprehensively elucidated. This study aimed to investigate the role of Tlr4-mediated mechanisms in oxLDL induced foam-cell formation within VSMCs. Methods: After incubated with different dose of oxLDL, the lipid, reactive oxygen species (ROS) accumulation and foam-cell phenotype of the VSMCs were detected. The alteration of Tlr family, ROS and lipid accumulation regulators including the Src kinase, Nox2, Nox4, Mnsod and sirtuins were measured. Then the Tlr4 was knock down and underlying cellular change and altered molecules were detected. Results: We showed that oxLDL induced foam-cell like phenotype in VSMCs and led to lipid and ROS accumulation in a dose-dependent manner. OxLDL induced the strongest upregulation of Tlr4 in the Tlrs family and initiated change of Src activation, Nox2, Mnsod, sirt1 and sirt3 expression. The effect of oxLDL was abolished by Tlr4 knockdown. Furthermore, knocking down of Tlr4 reduced Src activation and led to restored Sirt1/Sirt3 expression. Moreover, inhibiting or knocking down the Src kinase diminished lipid accumulation in VSMCs under oxLDL treatment. And overexpression of Sirt1/3 relieved the oxLDL induced ROS accumulation and foam-cell phenotype in VSMCs.Conclusions: These results demonstrated that Tlr4 is a critical regulator in oxLDL induced foam cell formation of VSMCs via mediating Src kinase as well as Sirt1 and Sirt3. Beyond the role of Tlr4 in inflammation response of VSMCs, we provide an integrated mechanism about TLR4 in VSMCs phenotype transition under oxLDL stimulation.

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Section: Discussionmentioning

confidence: 99%

Toll-Like Receptor 4 Mediated Oxidized Low-Density Lipoprotein-Induced Foam Cell Formation in Vascular Smooth Muscle Cells

Chen

Xue

Cao

et al. 2020

Preprint

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“…The density and size of these particles are similar to those of plasma HDL [ 148 ]. ABCA1 contributes to cholesterol homeostasis and participates in the pathophysiology of neurological diseases involving the accumulation of proteins in brain cells, such as traumatic brain injury, stroke sequelae, Parkinson’s disease, and Alzheimer’s disease (AD) [ 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 ].…”

Section: Abca1 In Neurological Diseasementioning

confidence: 99%

The Role of the ATP-Binding Cassette A1 (ABCA1) in Human Disease

Jacobo-Albavera

Domínguez‐Pérez

Medina-Leyte

et al. 2021

IJMS

100

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Cholesterol homeostasis is essential in normal physiology of all cells. One of several proteins involved in cholesterol homeostasis is the ATP-binding cassette transporter A1 (ABCA1), a transmembrane protein widely expressed in many tissues. One of its main functions is the efflux of intracellular free cholesterol and phospholipids across the plasma membrane to combine with apolipoproteins, mainly apolipoprotein A-I (Apo A-I), forming nascent high-density lipoprotein-cholesterol (HDL-C) particles, the first step of reverse cholesterol transport (RCT). In addition, ABCA1 regulates cholesterol and phospholipid content in the plasma membrane affecting lipid rafts, microparticle (MP) formation and cell signaling. Thus, it is not surprising that impaired ABCA1 function and altered cholesterol homeostasis may affect many different organs and is involved in the pathophysiology of a broad array of diseases. This review describes evidence obtained from animal models, human studies and genetic variation explaining how ABCA1 is involved in dyslipidemia, coronary heart disease (CHD), type 2 diabetes (T2D), thrombosis, neurological disorders, age-related macular degeneration (AMD), glaucoma, viral infections and in cancer progression.

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“…Factors participating in the atherosclerotic process have been identified, among them: genetic predisposition, hyperlipidemia, metabolic dysregulation (obesity, diabetes), hypertension and smoking ( 4 ). A role for microorganisms has also been hypothesized, at least for the initial stages of atherosclerosis ( Figure 1 , topic 1) ( 5 – 8 ). The first steps of atherogenesis are characterized by endothelium activation and changes in lipid permeability.…”

Section: Introductionmentioning

confidence: 99%

Purinergic Signaling in Controlling Macrophage and T Cell Functions During Atherosclerosis Development

et al. 2021

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Atherosclerosis is a hardening and narrowing of arteries causing a reduction of blood flow. It is a leading cause of death in industrialized countries as it causes heart attacks, strokes, and peripheral vascular disease. Pathogenesis of the atherosclerotic lesion (atheroma) relies on the accumulation of cholesterol-containing low-density lipoproteins (LDL) and on changes of artery endothelium that becomes adhesive for monocytes and lymphocytes. Immunomediated inflammatory response stimulated by lipoprotein oxidation, cytokine secretion and release of pro-inflammatory mediators, worsens the pathological context by amplifying tissue damage to the arterial lining and increasing flow-limiting stenosis. Formation of thrombi upon rupture of the endothelium and the fibrous cup may also occur, triggering thrombosis often threatening the patient’s life. Purinergic signaling, i.e., cell responses induced by stimulation of P2 and P1 membrane receptors for the extracellular nucleotides (ATP, ADP, UTP, and UDP) and nucleosides (adenosine), has been implicated in modulating the immunological response in atherosclerotic cardiovascular disease. In this review we will describe advancements in the understanding of purinergic modulation of the two main immune cells involved in atherogenesis, i.e., monocytes/macrophages and T lymphocytes, highlighting modulation of pro- and anti-atherosclerotic mediated responses of purinergic signaling in these cells and providing new insights to point out their potential clinical significance.

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Infection and atherosclerosis: TLR-dependent pathways

Cited by 110 publications

References 182 publications

Toll-Like Receptor 4 Mediated Oxidized Low-Density Lipoprotein-Induced Foam Cell Formation in Vascular Smooth Muscle Cells

Toll-Like Receptor 4 Mediated Oxidized Low-Density Lipoprotein-Induced Foam Cell Formation in Vascular Smooth Muscle Cells

The Role of the ATP-Binding Cassette A1 (ABCA1) in Human Disease

Purinergic Signaling in Controlling Macrophage and T Cell Functions During Atherosclerosis Development

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