Endogenous TLR ligands

Evidence from diverse sources and experimental models has provided a wealth of data suggesting that TLRs could affect atherosclerosis in multiple ways. Minimally modified LDL (MM-LDL), a strong inducer of proinflammatory cytokines and chemokines with pro-atherogenic potential [5, 34], is recognized by both TLR4 and CD14 on macrophages, and interaction of this lipoprotein with TLR4 leads to actin polymerization and macrophage spreading [35, 36]. Data on the potential role of other TLRs in atherosclerotic lesions is still largely unknown.

Furthermore, evidence for an involvement of an immune response towards heat shock proteins (HSPs) in the development of arteriosclerosis is accumulating (for a recent review, see [37]). Heat shock proteins are among the most highly conserved protein families and are ubiquitously expressed in almost all mammalian tissues. In particular prokaryotic and human HSP60 share a high amino acid sequence homol-ogy (>70%). Immunologic cross-reaction between bacterial (e.g., Chlamydial) and human HSP60, which has been detected on the surface of stressed endothelial cells, might be involved in atherogenesis. Both, bacterial and human HSP60 signal through TLR4 and/or TLR2 and lead to the activation of NF-KB-dependent proinflammatory gene targets [38-41]. Chlamydial HSP60 was shown to lead to human SMCs proliferation in a TLR4-dependent manner [41]. Nasal vaccination with mycobacterial HSP65 has been demonstrated to reduce inflammation and decrease atherosclerosis in aortic arches in LDL receptor-deficient mice [42]. Furthermore, fragments of fibronectin have been associated with tissue injury and tissue remodeling in response to inflammation, and the extra domain A of fibronectin (EDA) can be recognized by TLR4 [43]. Depletion of EDA results in decreased atherosclerosis in apoE-/- mice [44], suggesting that the role of TLR4 during atherogenesis is mul-tifaceted and might include both endogenous (MM-LDL, HSP60, EDA) and exogenous (ligands derived from various pathogens) ligands.

Ox-PAPC (oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphoryl-choline), a bioactive component of mildly oxidized LDL [45], utilizes TLR4 as a sig-

naling receptor, but also has a direct effect on TLR signaling. Ox-PAPC inhibits the activation of IL-8 and MCP-1 by TLR4 and TLR2 ligands via their corresponding receptor in endothelial cells or macrophages by disrupting lipid rafts/caveolae [24]. The integrity of lipid rafts/caveolae is thought to be essential to LPS-induced cellular activation, since raft-disrupting drugs inhibit LPS-induced cytokine secretion [46]. Inhibition of TLRs by Ox-PAPC might contribute to downregulation of the acute-phase response to bacterial lipid-containing products and propagate a more chronic inflammation typical of the progression of atherosclerosis.

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