Toll in the vessel wall--for better or worse?

P attern recognition receptors detect danger signals such as pathogen-associated molecular patterns. Among such detectors, the membrane-bound receptors of the Toll-like receptor (TLR) family can detect all kinds of pathogens and play an important role in host defense (1). Not surprisingly, TLRs are also involved in chronic inflammatory diseases such as arthritis, colitis, and atherosclerosis. A report in PNAS provides insights into the role of TLRs in vascular biology (2). Atherosclerosis, the cause of myocardial infarction and stroke, is a chronic inflammatory disease elicited by cholesterol accumulation in the artery wall (3). Innate as well as adaptive immunity contributes to inflammation in atherosclerosis, and a spectrum of TLRs are expressed in the human atherosclerotic plaque (4). Experiments in gene-targeted models show that certain TLRs impact on atherosclerosis in hypercholesterolemic mice (5, 6). Specifically, TLR2 and TLR4 ligations promote disease development, whereas ablation of these receptors reduces lesion size (7, 8). Thus, one could envisage that endotoxins released during infections with Gram-negative bacteria would ligate TLR4 in lesions, leading to accelerated atherosclerosis. Similarly, peptidoglycans of Gram-positive bacteria could promote atherosclerosis by ligating TLR2. These findings are of obvious interest, because certain bacterial infections have been suggested to promote cardiovascular disease. Viruses can be recognized by TLR3, which ligates dsRNA (9), TLR7 and TLR8, which bind certain ssRNA species, and TLR9, which is stimulated by unmethylated CpG DNA motifs. The effects of such signals are also of interest for cardiovascular disease, because certain viral infections have been associated with atherosclerosis. In addition, it is possible that endogenous danger signals could bind to TLR and trigger signaling cascades. For instance, TLR3 signaling can be activated by endogenous RNA molecules released during cell death (10, 11). However, little is known about the role of these TLRs in cardiovascular disease.