Unexpected protective role for Toll-like receptor 3 in the arterial wall

Abstract

The critical role of Toll-like receptors (TLRs) in mammalian host defense has been extensively explored in recent years. The capacity of about 10 TLRs to recognize conserved patterns on many bacterial and viral pathogens is remarkable. With so few receptors, cross-reactivity with self-tissue components often occurs. Previous studies have frequently assigned detrimental roles to TLRs, in particular to TLR2 and TLR4, in immune and cardiovascular disease. Using human and murine systems, we have investigated the consequence of TLR3 signaling in vascular disease. We compared the responses of human atheroma-derived smooth muscle cells (AthSMC) and control aortic smooth muscle cells (AoSMC) to various TLR ligands. AthSMC exhibited a specific increase in TLR3 expression and TLR3-dependent functional responses. Intriguingly, exposure to dsRNA in vitro and in vivo induced increased expression of both pro- and anti-inflammatory genes in vascular cells and tissues. Therefore, we sought to assess the contribution of TLR3 signaling in vivo in mechanical and hypercholesterolemia-induced arterial injury. Surprisingly, neointima formation in a perivascular collar-induced injury model was reduced by the systemic administration of the dsRNA analog Poly(I:C) in a TLR3-dependent manner. Furthermore, genetic deletion of TLR3 dramatically enhanced the development of elastic lamina damage after collar-induced injury. Accordingly, deficiency of TLR3 accelerated the onset of atherosclerosis in hypercholesterolemic ApoE −/− mice. Collectively, our data describe a protective role for TLR signaling in the vessel wall.

Toll in the vessel wall—for better or worse?

“…Interestingly, cells derived from atherosclerotic lesions responded more vigorously than cells derived from normal arteries in the study by Cole et al (2). Although the two cell types may not be directly comparable because of differences in conditions of isolation, the data point to an increased responsiveness to TLR3 agonists in the atherogenic environment.…”

“…When human coronary arteries were grafted into SCID mice, IFN-γ induced TLR3 expression and a vivid response to dsRNA (15). It is interesting to speculate that the enhanced TLR3 expression in atheroma cultures registered by Cole et al (2) may be because of the presence of IFN-γ derived from immune cells infiltrating plaques.…”

“…Unexpected Effects of TLR3 on Atherosclerosis Cole et al (2) surprisingly observe that TLR3-deficient Apoe −/− mice exhibited increased early atherosclerosis compared with TLR3-expressing mice under conditions where no exogenous TLR3 ligand was administered. Although the effect is relatively modest, it is puzzling.…”

“…In contrast, the effects of exogenously administered dsRNA depended on TLR3 ligation, because this protection was ablated in Tlr3 −/− mice. To extend their findings to the human condition, Cole et al (2) examine the response of human vascular smooth muscle cells to the TLR3 agonist. They registered a response of these cells to dsRNA, which induced expression of several adhesion molecules, chemokines, and inflammatory cytokines.…”

“…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).…”