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.