Toll-Like Receptor 4 Signalling and Its Impact on Platelet Function, Thrombosis, and Haemostasis

Abstract

Platelets are anucleated blood cells that participate in a wide range of physiological and pathological functions. Their major role is mediating haemostasis and thrombosis. In addition to these classic functions, platelets have emerged as important players in the innate immune system. In particular, they interact with leukocytes, secrete pro- and anti-inflammatory factors, and express a wide range of inflammatory receptors including Toll-like receptors (TLRs), for example, Toll-like receptor 4 (TLR4). TLR4, which is the most extensively studied TLR in nucleated cells, recognises lipopolysaccharides (LPS) that are compounds of the outer surface of Gram-negative bacteria. Unlike other TLRs, TLR4 is able to signal through both the MyD88-dependent and MyD88-independent signalling pathways. Notably, despite both pathways culminating in the activation of transcription factors, TLR4 has a prominent functional impact on platelet activity, haemostasis, and thrombosis. In this review, we summarise the current knowledge on TLR4 signalling in platelets, critically discuss its impact on platelet function, and highlight the open questions in this area.

Tissue factor over-expression in platelets of patients with anti-phospholipid syndrome: induction role of anti-β2-GPI antibodies

“…In addition, we show that, following anti-β2-GPI antibody triggering, NF-κB was activated. Although the role of NF-κB in platelets is still not completely understood, recent evidence strongly supports the view that NF-κB activation represents a key signaling pathway in the regulation of platelets physiology [16].…”

“…Although the role of NF-κB in platelets is still not completely understood, recent evidence strongly supports the view that NF-κB activation represents a key signaling pathway in the regulation of platelets physiology [16]. Although the role of NF-κB in platelets is still not completely understood, recent evidence strongly supports the view that NF-κB activation represents a key signaling pathway in the regulation of platelets physiology [16].…”

“…Thus, activation of the TLR-4 signaling pathway in platelets by anti-β2-GPI may have specific functional implications, playing a role in some pathological manifestations of the syndrome. Indeed, TLR-4 is able to signal through both MyD88-IRAK-dependent and -independent signaling pathways leading to the activation of transcription factors, with consequent functional effects on platelet activity, hemostasis and thrombosis [16].…”

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

“…These findings were simultaneously confirmed by Garraud et al., who demonstrated the expression of several members of the TLR family including TLR4 in human platelets and its down‐regulation by LPS‐mediated platelet activation . Since then, several groups have explored the in vitro effect of platelet TLR4 activation by LPS; however, there are still many controversies in the field …”

“…8 Since then, several groups have explored the in vitro effect of platelet TLR4 activation by LPS; however, there are still many controversies in the field. 9 Whereas some studies have shown that TLR4 activation by LPS induces platelet activation, most observed that this is not a direct effect but rather potentiates platelet responses elicited by classical agonists including aggregation, ATP release, P-selectin expression, and the formation of mixed aggregates between platelets and neutrophils. [10][11][12][13] It is worth mentioning that, among these studies, only the experiments by Nocella et al 13 were performed using LPS in the picogram range; all other studies required 10 times more LPS to achieve similar results.…”