Toll-Like Receptor 2 Linked to Atherosclerotic Damage


Image: Flickr - dawnzy
Image: Flickr - dawnzy
Atherosclerosis is caused by a build up of lipids, cholesterol, calcium, and cellular debris within the artery, resulting in plaque formation. This restricts the flow of blood and decreases oxygen supply to target organs, increasing the risk of cardiovascular diseases including heart attacks and stroke. The true incidence of atherosclerosis is difficult, if not impossible, to determine since it is predominantly asymptomatic, but the ensuing cardiovascular diseases are the leading cause of death in many Western societies. Risk factors for atherosclerosis include high blood pressure and a high fat diet and current non-surgical treatments, such as antihypertensive medicines and statins, focus on reducing these risks.

The precise mechanisms underlying atherogenesis are unclear but scientists at Imperial College London have now identified a pathway that plays a key role in the inflammation and matrix degradation characteristic of human atherosclerosis.

The researchers studied sections of carotid artery taken from 58 stroke patients and found that toll-like receptor 2 (TLR-2) was unusually active in the plaques. TLRs are expressed on immune cells and play a fundamental role in pathogen recognition and innate immunity, mediating release of cytokines and other inflammatory mediators. One arm of the TLR-induced inflammatory response is dependent on a signalling pathway that is mediated by the adaptor molecule, myeloid differentiation primary response gene 88 (MyD88), and the study showed that a dominant-negative form of MyD88 decreased the production of MCP-1, IL-8, IL-6, MMP-1 and MMP-3 as well as NF-κB activation in cell cultures prepared from the carotid arteries. TLR-2 neutralizing antibodies were also shown to inhibit NF-κB activation and significantly reduce MCP-1, IL-8, IL-6, MMP-1, MMP-2, MMP-3, and MMP-9 production. In contrast, an IL-1R antagonist, TLR-4 blocking antibodies, or overexpression of a dominant-negative form of the TLR-4 signalling adaptor, TRIF-related adaptor molecule, reduced NF-κB activity but did not have a broad impact on the production of the inflammatory mediators studied.

The authors hope that TLR-2 blockers might be developed to prevent or treat atherosclerosis and the resulting cardiovascular disease without compromising the ability to fight infection.

The study is published in the journal Circulation.

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