The Role of TLR2, TLR4, and TLR9 in the Pathogenesis of Atherosclerosis

Abstract

Toll-like receptors (TLRs) are key players in the pathogenesis of inflammatory conditions including coronary arterial disease (CAD). They are expressed by a variety of immune cells where they recognize pathogen-associated molecular patterns (PAMPs). TLRs recruit adaptor molecules, including myeloid differentiation primary response protein (MYD88) and TIRF-related adaptor protein (TRAM), to mediate activation of MAPKs and NF-kappa B pathways. They are associated with the development of CAD through various mechanisms. TLR4 is expressed in lipid-rich and atherosclerotic plaques. In TLR2−/− and TLR4−/− mice, atherosclerosis-associated inflammation was diminished. Moreover, TLR2 and TLR4 may induce expression of Wnt5a in advanced staged atheromatous plaque leading to activation of the inflammatory processes. TLR9 is activated by CpG motifs in nucleic acids and have been implicated in macrophage activation and the uptake of oxLDL from the circulation. Furthermore, TLR9 also stimulates interferon-α (INF-α) secretion and increases cytotoxic activity of CD4+ T-cells towards coronary artery tunica media smooth muscle cells. This review outlines the pathophysiological role of TLR2, TLR4, and TLR9 in atherosclerosis, focusing on evidence from animal models of the disease.

Platelet TLR4 at the crossroads of thrombosis and the innate immune response

“…Specifically, an association has been reported between the Asp299Gly TLR4 gene polymorphism with acute coronary events in men but not in women . In addition, there is evidence showing that TLR4 is associated with the initiation, progression, and eventual rupture of the atheroma plaque . Although these studies have mainly looked at TLR4 in monocytes and T lymphocytes, evidence showing that PAMPs and DAMPs interact with platelet TLR4 and trigger platelet activation clearly indicates that increased expression and/or functionality of platelet TLR4 might be involved in the pathogenesis of atherosclerosis and acute coronary events.…”

“…48 In addition, there is evidence showing that TLR4 is associated with the initiation, progression, and eventual rupture of the atheroma plaque. 49 Although these studies have mainly looked at TLR4 in monocytes and T lymphocytes, evidence showing that PAMPs and DAMPs interact with platelet TLR4 and trigger platelet activation clearly indicates that increased expression and/or functionality of platelet TLR4 might be involved in the pathogenesis of atherosclerosis and acute coronary events. In this sense, it has recently been reported that patients with unstable angina pectoris have enhanced expression of both platelet TLR2 and TLR4 compared to patients with stable angina pectoris and subjects with normal coronary arteries.…”

Wnt5a is involved in LOX‐1 and TLR4 induced host inflammatory response in peri‐implantitis

“…Zhang Y et al found that DKK1 induced by ox‐LDL suppressed LOX‐1 expression via the Wnt canonical signaling pathway in macrophages. Roshan MH et al found that Wnt5a expression was decreased in atherosclerosis‐associated inflammation following TLR2 and TLR4 knockout, while He X et al showed that the TLR4 pathway up‐regulated Wnt5a in mesenchymal stem cells treated with LPS. Furthermore, He W et al found that Wnt5a also activated NF‐κB in LPS‐stimulated human dental pulp stem cells in a TLR4/MyD88 dependent manner.…”

Prevention of TLR9 Pathway in Warm Ischemia in Porcine Donor Liver after Cardiac Death

“…Among the TLRs mediating inflammation, TLR2, TLR4 and TLR9 are related to ischemic injury [16]. Previous studies have demonstrated the involvement of TLR2 and TLR4 in hepatic ischemia [1], but the role of TLR9 in liver ischemia is not clear yet.…”