Researchers Discover Cause of Arterial Inflammation in Atherosclerosis

December 3, 2009

Researchers from Imperial College London have found the trigger that causes inflammation and artery damage in patients with atherosclerosis.

Researchers from Imperial College London have found the trigger that causes inflammation and artery damage in patients with atherosclerosis. According to a press release, the trigger is the receptor molecule TLR-2, which “lives on the surface of an immune cell,” switching it into “attack mode” in the presence of harmful molecules and stress. Research shows that TLR-2 “is unusually active in plaques in the carotid artery in the neck,” and that blocking the TLR-2 receptor prevents cells from producing molecules that cause inflammation and damage to the artery.

Study author Claudia Monaco, MD, PhD, from the Kennedy Institute of Rheumatology and Vascular Surgery at Imperial College London, said that this study “reveals the trigger for inflammation and tissue breakdown in artery plaques. We have also shown that this trigger mechanism can be blocked using antibodies. If we can find a way to successfully block these receptors in people, without reducing their ability to fight off infection, we could potentially develop a treatment for atherosclerosis.”

For the study, researchers assessed atherosclerotic sections of the carotid artery from 58 patients who had suffered a stroke. Analysis of the artery tissue showed that “the cells had produced an unusually large amount of inflammatory molecules and enzymes that damage arteries.”

The researchers cultivated the cells with “several different antibodies designed to block different receptors and molecules involved in the inflammation process,” revealing that “blocking TLR-2 using an antibody reduced the production of inflammation molecules and enzymes dramatically.”

Results from the study were published online ahead of print in Circulation. In the article abstract, the authors noted that a

dominant-negative form of myeloid differentiation primary response gene 88 (MyD88) decreased the production of monocyte chemotactic protein-1/CCL2, IL-8/CXCL8, IL-6, matrix metalloproteinase-1 (MMP-1), and MMP-3, as well as nuclear factor-kappaB activation 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- kappaB activity but did not have a broad impact on the production of the mediators studied.” In contrast, TLR-2 neutralizing antibodies “inhibited nuclear factor-kappaB activation and significantly reduced monocyte chemotactic protein-1/CCL2, IL-8/CXCL8, IL-6, and MMP-1, MMP-2, MMP-3, and MMP-9 production.”