Expression of Toll-like receptors on human platelets

Shiraki, Rio; Inoue, N.; Kawasaki, Satoru; Takei, Atsushi; Kadotani, Makoto; Ohnishi, Yoshio; Ejiri, Junya; Kobayashi, Seiichi; Hirata, Ken‐ichi; Kawashima, Seinosuke; Yokoyama, Mitsuhiro

doi:10.1016/j.thromres.2004.03.023

Cited by 222 publications

(190 citation statements)

References 14 publications

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“…32 A recent study reported that human platelets also express both TLR1 and TLR6. 33 These data support the concept that TLRs play an important role in the pathophysiological relationship between innate immunity and atherosclerotic disease. A recent study demonstrated that TLR2 and TLR4 are ubiquitously present in 6 different human vessels (aorta, subclavian, carotid, mesenteric, iliac, and temporal arteries), TLR7 and TLR9 are infrequent, and TLR1, TLR3, TLR5, and TLR8 are selectively expressed.…”

supporting

confidence: 71%

Immune System and Atherosclerotic Disease

Shimada

2009

Circ J

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supporting

confidence: 71%

Immune System and Atherosclerotic Disease

Shimada

2009

Circ J

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“…10,11 They have been shown to express the TLRs, a major class of pattern-recognition receptors involved in the innate immune response through the recognition of microbial structures conserved among species (pathogen-associated molecular patterns) and of endogenous molecules released from damaged cells (damageassociated molecular patterns). 12 TLR1, TLR2, TLR4, TLR6, TLR8, and TLR9 have been found on human platelets 13,14 and were shown to be functional. For example, the TLR2 agonist PAM 3 -CSK4 induces platelet adhesion, degranulation, aggregation, and the formation of platelet-neutrophil aggregates, 15 and lipopolysaccharide (LPS), a TLR4 agonist, induces platelet P-selectin expression and ATP secretion and primes platelets to aggregate in response to low-dose thrombin.…”

Section: Introductionmentioning

confidence: 95%

Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4

Semeraro

Ammollo

Morrissey

et al. 2011

Blood

703

661

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The release of histones from dying cells is associated with microvascular thrombosis and, because histones activate platelets, this could represent a possible pathogenic mechanism. In the present study, we assessed the influence of histones on the procoagulant potential of human platelets in platelet-rich plasma (PRP) and in purified systems. Histones dose-dependently enhanced thrombin generation in PRP in the absence of any trigger, as evaluated by calibrated automated thrombinography regardless of whether the contact phase was inhibited. Activation of coagulation required the presence of fully activatable platelets and was not ascribable to platelet tissue factor, whereas targeting polyphosphate with phosphatase reduced thrombin generation even when factor XII (FXII) was blocked or absent. In the presence of histones, purified polyphosphate was able to induce thrombin generation in plasma independently of FXII. In purified systems, histones induced platelet aggregation; P-selectin, phosphatidylserine, and FV/Va expression; and prothrombinase activity. Blocking platelet TLR2 and TLR4 with mAbs reduced the percentage of activated platelets and lowered the amount of thrombin generated in PRP. These data show that histone-activated platelets possess a procoagulant phenotype that drives plasma thrombin generation and suggest that TLR2 and TLR4 mediate the activation process. (Blood. 2011;118(7):1952-1961) IntroductionHistones are cationic proteins that associate with DNA in nucleosomes and are involved in chromatin remodeling and regulation of gene transcription. Despite their physiologic nuclear localization, nucleosomes have been found in the circulation of both healthy subjects and patients, where they can be released from dying cells 1 or actively secreted by activated inflammatory cells (neutrophils, basophils, and mast cells) in the form of "extracellular traps," complex structures of DNA strands, histones, and cell-specific granule proteins. 2,3 High blood levels of nucleosomes have been detected in several inflammatory, ischemic, autoimmune, and neoplastic diseases 4 ; in some cases, a correlation with disease severity has been found. 5 Whether extracellular nucleosomes are merely bystanders or active mediators in disease and which role histones play are important emerging questions. Histones are known to possess cytotoxic properties against both microorganisms 6 and eukaryotic cells. 7 Xu et al 8 reported that extracellular histones behave as late mediators of cell damage and organ dysfunction during the hyperinflammatory reaction that characterizes sepsis, as shown by the efficacy of a neutralizing antibody against histone H4 in reducing mortality in several experimental models of murine sepsis. Moreover, direct injection of histones into mice resulted in death with pathologic lesions suggestive of a massive prothrombotic response similar to that found in sepsis, including diffuse microvascular thrombosis, fibrin and platelet deposition in the lung alveoli, and intra-alveolar hemorrhage. Fuchs et al 9 rec...

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“…Within the last 15 years it became more and more evident that nonnucleated platelets are also implicated in the adaptive [2] as well as being components of the innate immune system [3,4], the latter which came into focus by the discovery that platelets express Toll-like receptors (TLRs) [5], of which TLR4, TLR2, and TLR9 were found to be the most abundant [6,7]. TLR2, in particular, forms heterodimers with TLR1 or TLR6, which is the prerequisite to recognize a wide spectrum of microbial pathogen-associated molecules such as peptidoglycans and lipopeptides [8,9].…”

Section: Introductionmentioning

confidence: 99%