Abstract
It is now thought that atherosclerosis, although due to increased plasma lipids, is mainly the consequence of a complicated inflammatory process, with immune responses at the different stages of plaque development. Increasing evidence points to a significant role of Toll-like receptor 4 (TLR4), a key player in innate immunity, in the pathogenesis of atherosclerosis. This study aimed to determine the effects on TLR4 activation of two reactive oxidized lipids carried by oxidized low-density lipoproteins, the oxysterol 27-hydroxycholesterol (27-OH) and the aldehyde 4-hydroxynonenal (HNE), both of which accumulate in atherosclerotic plaques and play a key role in the pathogenesis of atherosclerosis. Secondarily, it examined their potential involvement in mediating inflammation and extracellular matrix degradation, the hallmarks of high-risk atherosclerotic unstable plaques. In human promonocytic U937 cells, both 27-OH and HNE were found to enhance cell release of IL-8, IL-1β, and TNF-α and to upregulate matrix metalloproteinase-9 (MMP-9) via TLR4/NF-κB-dependent pathway; these actions may sustain the inflammatory response and matrix degradation that lead to atherosclerotic plaque instability and to their rupture. Using specific antibodies, it was also demonstrated that these inflammatory cytokines increase MMP-9 upregulation, thus enhancing the release of this matrix-degrading enzyme by macrophage cells and contributing to plaque instability. These innovative results suggest that, by accumulating in atherosclerotic plaques, the two oxidized lipids may contribute to plaque instability and rupture. They appear to do so by sustaining the release of inflammatory molecules and MMP-9 by inflammatory and immune cells, for example, macrophages, through activation of TLR4 and its NF-κB downstream signaling.
Highlights
Atherosclerosis is a multifactorial disease characterized by the accumulation of lipids in the vascular wall
To investigate whether 27-OH and HNE affect the activation of Toll-like receptor 4 (TLR4), human promonocytic U937 cells were incubated with these two components of oxidized LDLs (oxLDLs)
The effects of 27-OH and HNE on TLR4 expression were quantified by real-time RT–PCR
Summary
Atherosclerosis is a multifactorial disease characterized by the accumulation of lipids in the vascular wall. Several studies have suggested that atherogenesis is dependent on the innate immune response and that monocytes/macrophages, as well as T lymphocytes, all of which are cellular components of innate immunity, play predominant roles in atherosclerosis. Activation of these immune cells leads to a cascade of pro-inflammatory molecules release, which induces an inflammatory state in the vessel wall, with subsequent activation of the other arterial wall cells. Macrophages express receptors that recognize molecular patterns commonly found on pathogens (PAMPs: pathogenassociated molecular patterns) but foreign to mammalian organisms and are important in innate immunity In this context, the type I transmembrane receptors known as Toll-like receptors (TLRs) are the innate immune receptors that have been most extensively studied and characterized. TLRs, are expressed on macrophages and on the other cells commonly found in the arterial wall (Seneviratne et al, 2012)
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