TLR expression in atherosclerotic lesions

Several reports have documented the expression of TLR4, TLR1, TLR2 and to a lesser extent TLR5 in both human plaques and murine models of atherosclerosis [22, 23], where they appear to be mainly expressed by macrophages and endothelial cells. Moreover, TLR4 expression in macrophages is upregulated by oxidized LDL, a proinflammatory and pro-atherogenic lipoprotein, but not by native LDL [22, 24]. Furthermore, it has been shown that in addition to endothelial cells and macrophages, murine vascular smooth muscle cells also express TLR2 and TLR4/MD-2 while human arterial smooth muscle cells express only TLR4/MD-2 [25, 26]. TLR expression might also be influenced by and dependent on local shear stress. In vitro data have shown that in particular TLR2 is downregulated under laminar flow [27]. Stimulation with the appropriate TLR ligand induces signaling that promotes a proinflammatory phenotype in vascular SMCs, which suggests that these cells may potentially play an active role in vascular inflammation via the release of chemokines and proinflammatory cytokines. In recent years DCs have become more and more appreciated as a key player in the development of atherosclerosis [28, 29]. Vascular DCs, which are present in small numbers in the suben-dothelial layer of non-diseased arteries, become activated in early stages of athero sclerosis by signaling pathways most likely involving TLRs and migrate into atherosclerotic plaques. In the atherosclerotic plaques the DCs cluster with T cells suggesting presentation of antigens such as HSP70 and MM-LDL [30, 31]. DCs locate particularly in rupture-prone regions within the atherosclerotic plaques and are in highest abundance in vulnerable plaques, which leads to the conclusion that DCs might contribute to plaque destabilization [30]. Dislipidemia has been shown to alter DCs function in ApoE-deficient mice [32]. While in the early stages of atherosclerosis the number of Langerhans cells in the skin is reduced, later on the migration of DCs to the lymph nodes is impaired in ApoE-deficient mice, which explains high susceptibility to infection in these mice [33].

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