2009 George L. Duff Memorial Lecture—The Toll of Toll-Like Receptors on Atherosclerosis
Atherosclerosis is an inflammatory disease. Atherosclerotic lesions are foci of vessel wall inflammation. Lesions begin, very early in life, as fatty streaks, progressing to vulnerable obstructive lesions under the influence of both genetic and lifestyle insults. During a human lifetime that elapses between fatty streak formation and overt disease, many events can accelerate lesion progression. Genetic diseases, notably hypercholesterolemia, lead to severe disease. Lifestyle choices, which include smoking, obesity, and excessive quiescence, also make significant contributions to disease progression. Finally, inflammatory disease elsewhere in the body, ranging from periodontitis to autoimmune disease, can have an exacerbating effect as well. Toll-like receptors are a key mechanistic link between chronic inflammation and atherosclerosis. However, the factors that promote atherosclerotic lesion development do not do so uniformly throughout the arterial tree.
Lesions form first at sites of disturbed blood flow. Such sites are at vessel bifurcations and at the lesser curvature of the aortic arch. These sites display an inflamed phenotype even in the absence of any other exacerbating disease factors. This is due to the altered flow patterns at these sites within the aortic arch and the endothelial cell response to this disturbed flow. The biochemical mechanisms by which endothelial cells detect flow patterns are beginning to be understood. However, no particular atherosclerosis risk factor has been identified that would promote a proinflammatory phenotype only at arterial bifurcations and the lesser curvature of the aortic arch. Toll-like receptors (TLRs) may provide a clue.
TLRs are initiators of inflammation driven by agonists that can be either endogenous, such as sterile tissue damage, or exogenous, such as pathogens. Given the vicissitudes of daily life, TLRs likely initiate appropriate inflammatory responses every day. The majority of these are beneficial, promoting healing and homeostasis, but occasionally, inappropriate TLR activation causes pathology.
Bone marrow transplantation experiments demonstrate that leukocytes do not participate in the early atheroprotective inflammatory responses observed in TLR-deficient mice exposed to only endogenous agonists, but do participate in the proatherogenic responses to an exogenous agonist. We hypothesize that the exacerbation of disease progression mediated by endogenous activation of TLR receptors in endothelial cells is a disease of the arteries that is an “inside-out” (blood–lumen–endothelial cell–intima) phenomenon. In contrast, the accelerated disease mediated by exogenous activation of TLR receptors on circulating leukocytes is an “inside-out” and an “outside-in” disease phenomenon (leukocytes–vasa vasorum–adventia to media).