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

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-kappa B 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-kappa B activity but did not have a broad impact on the production of the mediators studied. In contrast, TLR-2 neutralizing antibodies inhibited nuclear factor-kappa B 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. (Circulation. 2009; 120: 2462-2469.)