Toll-Like Receptor-2 Mediates Inflammation and Matrix Degradation in Human Atherosclerosis

Abstract

Background— Inflammation and matrix degradation are the hallmarks of high-risk atherosclerosis that leads to myocardial infarction and stroke. Toll-like receptors (TLRs), key players in innate immunity, are upregulated in atherosclerotic lesions, but their functional role in human atherosclerosis is unknown. We explored the effects of blocking TLR-2, TLR-4, and myeloid differentiation primary response gene 88 (MyD88), a signaling adaptor shared by most TLRs and interleukin-1 receptor (IL-1R), in an in vitro model of human atherosclerosis. Methods and Results— Carotid endarterectomies were obtained from patients with symptomatic carotid disease. Cells were isolated via enzymatic tissue dissociation and cultured in the presence or absence of TLR signaling blockers. A dominant-negative form of MyD88 (MyD88 DN ) decreased the production of monocyte chemotactic protein-1/CCL2 ( P =0.000), IL-8/CXCL8 ( P =0.006), IL-6 ( P =0.002), matrix metalloproteinase-1 (MMP-1; P =0.002), and MMP-3 ( P =0.000), as well as nuclear factor-κB activation ( P <0.05) in atheroma cell cultures. IL-1R antagonist, TLR-4 blocking antibodies, or overexpression of a dominant-negative form of the TLR-4 signaling adaptor TRIF-related adaptor molecule reduced nuclear factor-κB activity but did not have a broad impact on the production of the mediators studied. In contrast, TLR-2 neutralizing antibodies inhibited nuclear factor-κB activation ( P <0.05) and significantly reduced monocyte chemotactic protein-1/CCL2 ( P =0.000), IL-8/CXCL8 ( P =0.009), IL-6 ( P =0.000), and MMP-1 ( P =0.000), MMP-2 ( P =0.004), MMP-3 ( P =0.000), and MMP-9 ( P =0.006) production. Conclusions— Our data indicate that TLR-2 signaling through MyD88 plays a predominant role in inflammation and matrix degradation in human atherosclerosis. TLR-2 blockade may represent a therapeutic strategy for atherosclerosis and its complications.

The serum from dialysis patients with acute coronary syndrome up-regulates the expression of TLR2 and its downstream effectors in human renal glomerular endothelial cells

“…12,13 Moreover, unlike TLR4 blockade, neutralizing TLR2 can inhibit the expression of NF-iB and the release of interleukin-6 (IL-6), IL-8, and matrix metalloproteinases. 14 Compared to TLR4, up-regulation of TLR2 had much more significant influence on plaque varying from vulnerability to rupture, 14 which was consistent with study by Mullick's et al, 15 that higher expression of TLR2 was detected in artery lesion-prone area of mouse. TLR2 modulates inflammatory cascade.…”

Oxidized Low Density Lipoprotein Induces Bone Morphogenetic Protein-2 in Coronary Artery Endothelial Cells via Toll-like Receptors 2 and 4

“…Native LDL and electronegative LDL increase the expression and release of interleukin (IL)-8, monocyte chemoattractant protein-1, and IL-6 in human umbilical artery endothelial cells (6). TLR2 and TLR4 play important roles in the vascular inflammatory response and are involved in the initiation and progression of atherosclerosis (7)(8)(9)(10). Increased endothelial expression of TLR2 at sites of disturbed blood flow exacerbates early atherogenic events (11).…”

Contrast Enhanced Ultrasonography and Carotid Plaque Imaging: from the Hemodynamic Evaluation to the Detection of Neoangiogenesis - The New Approach to the Identification of the Unstable Plaque: from Morphology to Patophysiology

“…Consequently, there is an important need to identify if other elements play a key role in the progression and embolism from carotid plaques. Nowadays, the importance of inflammation and inflammatory markers has been claimed as a fundamental factor involved in the development and progression of the atherosclerotic plaques; furthermore, the association between inflammation, atherosclerosis progression and cardiovascular events have been well established for coronary and carotid artery diseases (Libby, 2002;Ridker, 2003, Monaco 2009, Monaco 2010, Shalhoub 2009. Histological studies have observed that stable plaques are indeed characterized by a chronic inflammatory infiltrate, whereas vulnerable and ruptured plaques are characterized by an active inflammation and "plaque activity" processes involved in the thinning of the fibrous cap, predisposing to plaque rupture (de Nooijer, 1996;Spagnoli, 2004;Spagnoli, 2007).…”