Toll-Like Receptors, Their Ligands, and Atherosclerosis

Abstract

Atherosclerosis is a disease characterized by inflammation in the arterial wall. Atherogenesis is dependent on the innate immune response involving activation of Toll-like receptors (TLRs) and the expression of inflammatory proteins. TLRs, which recognize various pathogen-associated molecular patterns, are expressed in various cell types within the atherosclerotic plaque. Microbial agents are associated with an increased risk of atherosclerosis and this is, in part, due to activation of TLRs. Recently considerable evidence has been provided suggesting that endogenous proteins promote atherosclerosis by binding to TLRs. In this review, we describe the role of TLRs in atherosclerosis with particular emphasis on those atherogenic endogenous proteins that have been implicated as TLR ligands.

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“…46 TLR signaling leads to activation of transcription factors, such as nuclear factor-κB, that promote proinflammatory activity, contributing to the development of phenotypically distinct foam cells. 21,43,[47][48][49][50][51] First, TLRs induce foam cell formation by increasing the uptake of lipoproteins and the storage of lipid (via increases in CD36, AP2, fatty acid-binding proteins, MyD88-adaptor-like, adipose differentiation-related protein, lipin 1, glycerol-3-phosphate acyltransferase 3, and diacylglycerol O-acyltransferase 2). 52,53 Second, TLRs decrease the delivery of cholesterol macrophages to high-density lipoprotein (HDL), the first step in reverse cholesterol transport (via decreases in macrophages ATP-binding cassette transporter subfamily A (ABCA)-1, ATP-binding cassette transporter subfamily G, scavenger receptor class B, member 1/CD36 antigen-like 1, and apolipoprotein E).…”

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“…HSP70 can interact with the VSMCs, the major producer of ECM proteins, through the TLR4. The authors demonstrated that extracellular HSP70 binds to human aorta smooth muscle cell TLR4, which upregulated the [273] ; with own modification).…”

“…TLR activation of the endothelium promoted lipid and leukocyte accumulation within lesions [75] . TLRs ligands are expressed in various cell types within the atherosclerotic plaque [273] . TLR1, TLR2, and TLR4 were upregulated in human atheroma with active NF-κB colocalizing with TLR2 and TLR4 in the plaque [263] .…”

“…Stimulation with heparan sulfate induced dendritic cells (DCs) to secrete proinflammatory cytokines, such as TNF-α and IL-6, an effect that was TLR4 dependent [273,274] . DCs phenotypically and functionally matured in response to heparan sulfate, an effect that was abrogated when TLR4 was inhibited [275] .…”

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“…Wu et al [6] further found an increased collagen and elastin plaque content indicating a more stable plaque, while macrophage infiltration, the expression of cathepsin S protein (CatS) and toll-like receptor (TLR) 2 were reduced. TLR play an important role in the innate immune system and several lines of evidence indicate an association with atherosclerosis [8]. CatS is an excreted lysosomal protease which is linked to extracellular matrix degradation such as elastin and collagen and therefor potentially responsible for plaque destabilization [9].…”