Platelet TLR4

Sun, Zhongjie

doi:10.1161/circresaha.114.303945

Cited by 11 publications

(6 citation statements)

References 17 publications

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“…vWF is immobilised on collagen, and its association with GPIb-V-IX, a large glycoprotein (GP) complex, represents the initial interaction between platelets and the damaged vessel. This interaction slows down the platelets enabling them to interact with the exposed collagen via GPVI and platelet activation to ensue [ 57 – 59 ]. Binding of collagen to GPVI promotes an intracellular signalling cascade involving tyrosine kinase-mediated (e.g., Syk) activation of PLC γ 2.…”

Section: Tlr4 Signalling In Plateletsmentioning

confidence: 99%

“…Furthermore, activation of platelets leads to degranulation and the secretion of adenosine diphosphate (ADP) and the synthesis and release of thromboxane A 2 (TxA 2 ), resulting in the activation of more platelets and recruitment of them to the thrombus [ 57 – 59 ]. Moreover, prothrombin is cleaved into thrombin following interactions involving tissue factor, factor VIIa, and factor Xa on the activated platelet surface.…”

Section: Tlr4 Signalling In Plateletsmentioning

confidence: 99%

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

Vallance

Zeuner

Williams

et al. 2017

Mediators of Inflammation

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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.

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Section: Tlr4 Signalling In Plateletsmentioning

confidence: 99%

Section: Tlr4 Signalling In Plateletsmentioning

confidence: 99%

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

Vallance

Zeuner

Williams

et al. 2017

Mediators of Inflammation

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“…Aberrant expression of these downstream signaling proteins cause a mitochondrial metabolic abnormality that plays a pathophysiological role in PAH. Moreover, RNAi of CF6 effectively prevented macrophage infiltration, which is involved in the development of PAH-associated vascular lesions and has been well documented in humans [ 43 , 44 ]. This suggests that CF6 plays a critical role in the inflammation process of PAH; however, the complex mechanism remains poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Lung-specific RNA interference of coupling factor 6, a novel peptide, attenuates pulmonary arterial hypertension in rats

Yin

You

et al. 2016

Respir Res

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BackgroundPulmonary arterial hypertension (PAH) is a progressive and life-threatening disease associated with high morbidity and mortality rates. However, the exact regulatory mechanism of PAH is unknown. Although coupling factor 6 (CF6) is known to function as a repressor, its role in PAH has not been explored. Here, we investigated the involvement of endogenous CF6 in the development of PAH.MethodsPAH was induced with monocrotaline (MCT), as demonstrated by significant increases in pulmonary artery pressure and vessel wall thickness. The adeno-associated virus (AAV) carrying CF6 short hairpin RNA (shRNA) or control vector (2×1010 gp) was intratracheally transfected into the lungs of rats 2 weeks before or after MCT injection.ResultsA 2-6-fold increase in CF6 was observed in the lungs and circulation of the MCT-injected rats as confirmed by qRT-PCR and ELISA. Immunohistochemistry analysis revealed a small quantity of CF6 localized to endothelial cells (ECs) under physiological conditions spread to surrounding tissues in a paracrine manner in PAH lungs. Notably, CF6 shRNA effectively inhibited CF6 expression, abolished lung macrophage infiltration, reversed endothelial dysfunction and vascular remodeling, and ameliorated the severity of pulmonary hypertension and right ventricular dysfunction at 4 weeks both as a pretreatment and rescue intervention. In addition, the circulating and lung levels of 6-keto-PGF1a, a stable metabolite of prostacyclin, were reversed by CF6 inhibition, suggesting that the effect of CF6 inhibition may partly be mediated through prostacyclin.ConclusionsCF6 contributes to the pathogenesis of PAH, probably in association with downregulation of prostacyclin. The blockage of CF6 might be applied as a novel therapeutic approach for PAH and PA remodeling.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-016-0409-5) contains supplementary material, which is available to authorized users.

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“…Activation of TLR4 has been demonstrated to regulate MMP-9 production in lungs after hypoxia exposure, increasing ECM degradation and PASMC migration and proliferation (Young et al, 2010). PA ECs also release TLR4 endogenous agonists, such as HMGB1, which activate platelets and stimulate their aggregation at the injured/stressed PA sites (Bauer et al, 2013;Sun, 2014). The TLR4-activated platelets produce and secrete vasoactive substances (5-HT and TxA 2 ), mitogenic and growth factors (PDGF, TGF-β and VEGF) and proinflammatory cytokines (IL-1α, IL-1β and TNF-α) (Bauer et al, 2013;Sun, 2014).…”

Section: Pulmonary Hypertensionmentioning

confidence: 99%

“…PA ECs also release TLR4 endogenous agonists, such as HMGB1, which activate platelets and stimulate their aggregation at the injured/stressed PA sites (Bauer et al, 2013;Sun, 2014). The TLR4-activated platelets produce and secrete vasoactive substances (5-HT and TxA 2 ), mitogenic and growth factors (PDGF, TGF-β and VEGF) and proinflammatory cytokines (IL-1α, IL-1β and TNF-α) (Bauer et al, 2013;Sun, 2014). HMGB1 has also been shown to promote both pulmonary vascular remodelling and right ventricular hypertrophy through stimulation of TLR4 (Hilbert et al, 2017).…”

Section: Pulmonary Hypertensionmentioning

confidence: 99%

Targeting toll‐like receptor 4 signalling pathways: can therapeutics pay the toll for hypertension?

Nunes

Oliveira

Mowry

et al. 2018

British J Pharmacology

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The immune system plays a prominent role in the initiation and maintenance of hypertension. The innate immune system, via toll-like receptors (TLRs), identifies distinct signatures of invading microbes and damage-associated molecular patterns and triggers a chain of downstream signalling cascades, leading to secretion of pro-inflammatory cytokines and shaping the adaptive immune response. Over the past decade, a dysfunctional TLR-mediated response, particularly via TLR4, has been suggested to support a chronic inflammatory state in hypertension, inducing deleterious local and systemic effects in host cells and tissues and contributing to disease progression. While the underlying mechanisms triggering TLR4 need further research, evidence suggests that sustained elevations in BP disrupt homeostasis, releasing endogenous TLR4 ligands in hypertension. In this review, we discuss the emerging role of TLR4 in the pathogenesis of hypertension and whether targeting this receptor and its signalling pathways could offer a therapeutic strategy for management of this multifaceted disease.

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Platelet TLR4

Cited by 11 publications

References 17 publications

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

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

Lung-specific RNA interference of coupling factor 6, a novel peptide, attenuates pulmonary arterial hypertension in rats

Targeting toll‐like receptor 4 signalling pathways: can therapeutics pay the toll for hypertension?

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