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

Schattner, Mirta

doi:10.1002/jlb.mr0618-213r

Cited by 67 publications

(70 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In sepsis, platelets can be stimulated by LPS via TLR4, resulting in primed platelet activation elicited by other agonists [29,30]. Hence, there is a key role of the TLR4 receptor in the modulation of platelet phenotype in sepsis [13,27]. On the other hand, severe inflammation via TLR2 also regulates MK function that affects platelet production and function with enhanced GPIb and COX-2 protein expression [14]; however, no data has been published about TLR4 in this context.…”

Section: Discussionmentioning

confidence: 99%

“…Most TLR members, e.g., TLR4, are expressed on both platelets and megakaryocytes (MKs) [12]. Therefore, platelets participate in the amplified inflammatory and immune response during sepsis [13], while infection can also modulate thrombopoiesis via the TLR2 receptor [14]. Platelet hyperactivity may turn into thrombocytopenia because of neutrophil-dependent sequestration of activated platelets into the lungs in a TLR4-dependent manner [12].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Reduced miR-26b Expression in Megakaryocytes and Platelets Contributes to Elevated Level of Platelet Activation Status in Sepsis

Szilágyi

Fejes

Póliska

et al. 2020

IJMS

View full text Add to dashboard Cite

In sepsis, platelets may become activated via toll-like receptors (TLRs), causing microvascular thrombosis. Megakaryocytes (MKs) also express these receptors; thus, severe infection may modulate thrombopoiesis. To explore the relevance of altered miRNAs in platelet activation upon sepsis, we first investigated sepsis-induced miRNA expression in platelets of septic patients. The effect of abnormal Dicer level on miRNA expression was also evaluated. miRNAs were profiled in septic vs. normal platelets using TaqMan Open Array. We validated platelet miR-26b with its target SELP (P-selectin) mRNA levels and correlated them with clinical outcomes. The impact of sepsis on MK transcriptome was analyzed in MEG-01 cells after lipopolysaccharide (LPS) treatment by RNA-seq. Sepsis-reduced miR-26b was further studied using Dicer1 siRNA and calpain inhibition in MEG-01 cells. Out of 390 platelet miRNAs detected, there were 121 significantly decreased, and 61 upregulated in sepsis vs. controls. Septic platelets showed attenuated miR-26b, which were associated with disease severity and mortality. SELP mRNA level was elevated in sepsis, especially in platelets with increased mean platelet volume, causing higher P-selectin expression. Downregulation of Dicer1 generated lower miR-26b with higher SELP mRNA, while calpeptin restored miR-26b in MEG-01 cells. In conclusion, decreased miR-26b in MKs and platelets contributes to an increased level of platelet activation status in sepsis.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Reduced miR-26b Expression in Megakaryocytes and Platelets Contributes to Elevated Level of Platelet Activation Status in Sepsis

Szilágyi

Fejes

Póliska

et al. 2020

IJMS

View full text Add to dashboard Cite

show abstract

“…Notably, when blood from individuals with stable coronary artery disease and obese patients with atherosclerosis are stimulated with TLR ligands there is an increased cytokine response (25,26). Platelet TLR4 also has an important role in thrombosis (27), thus potentially linking toll-receptor expression to the hypercoagulability observed in COVID-19 patients (28). Considered together, changes in the expression of TLRs and other PRRs could have a key role in mediating the age-related inflammatory response during SARS CoV-2 infection.…”

Section: Discussionmentioning

confidence: 99%

AGE IS ASSOCIATED WITH INCREASED EXPRESSION OF PATTERN RECOGNITION RECEPTOR GENES ANDACE2, THE RECEPTOR FOR SARS-COV-2: IMPLICATIONS FOR THE EPIDEMIOLOGY OF COVID-19 DISEASE

Bickler

Cauvi

Fisch

et al. 2020

Preprint

View full text Add to dashboard Cite

Older aged adults and those with pre-existing conditions are at highest risk for severe COVID-19 associated outcomes. Using a large dataset of genome-wide RNA-seq profiles derived from human dermal fibroblasts (GSE113957) we investigated whether age affects the expression of pattern recognition receptor (PRR) genes and ACE2, the receptor for SARS-CoV-2. Older age was associated with increased expression of PRR genes, ACE2 and four genes that encode proteins that have been shown to interact with SAR2-CoV-2 proteins. Assessment of PRR expression might provide a strategy for stratifying the risk of severe COVID-19 disease at both the individual and population levels.

show abstract

“…In addition to PARs, platelets also express Toll‐like receptor 4 (TLR4), which recognizes lipopolysaccharide (LPS), another significant virulence factor characteristic of Gram‐negative pathogens such as P. gingivalis . Published evidence indicates that bacterial LPS activates platelets via TLR4 signaling . However, there appear to be considerable differences in platelets’ response to LPS from different bacterial species.…”

Section: Introductionmentioning

confidence: 99%

“…19 Published evidence indicates that bacterial LPS activates platelets via TLR4 signaling. 20,21 However, there appear to be considerable differences in platelets' response to LPS from different bacterial species. For example, LPS from Salmonella minnesota is reportedly a more potent platelet activator than LPS from Escherichia coli.…”

Section: Introductionmentioning

confidence: 99%

Porphyromonas gingivalis lipopolysaccharide activates platelet Cdc42 and promotes platelet spreading and thrombosis

Senini

Amara

Paul

et al. 2019

Journal of Periodontology

View full text Add to dashboard Cite

Background Periodontitis confers an increased risk for cardiovascular diseases, including thrombosis. However, the molecular mechanisms that potentially link periodontitis with thrombosis are undefined. Here we test the hypothesis that Gram‐negative periodontal infection promotes pathological platelet activation and amplifies shape change. We focus specifically on lipopolysaccharide (LPS) signaling to platelets. Methods Platelets were isolated from blood samples and allowed to spread on coverslips in the presence or absence of LPS purified from the periodontal pathogen Porphyromonas gingivalis. Platelets were fixed and stained with Alexa‐488‐phalloidin to label the actin cytoskeleton. The degree of platelet spreading and shape change was quantified by confocal microscopy. In a translational pilot study, blood samples were obtained from human subjects exhibiting generalized severe periodontitis (SP) or healthy periodontium (HP). Rotational thromboelastometry was used to quantify the rate of clot formation via the intrinsic coagulation pathway. Results LPS‐treated platelets exhibited significantly (P < 0.05) greater spreading and higher numbers of actin‐rich filopodia (cell extensions) than controls. We also found that LPS stimulation of platelets promoted the activation of Cdc42, the small GTPase responsible for filopodia formation. Exposure of whole blood samples to LPS significantly (P < 0.05) reduced clotting times. Blood from SP patients clotted significantly (P < 0.05) more rapidly and exhibited shorter partial thromboplastin times compared with HP controls. Conclusions This is the first study to suggest a mechanism by which LPS stimulation drives Cdc42 activation and platelet spreading. These data are consistent with the notion that periodontitis promotes accelerated clot formation and an increased risk of thrombosis.

show abstract

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

Cited by 67 publications

References 61 publications

Reduced miR-26b Expression in Megakaryocytes and Platelets Contributes to Elevated Level of Platelet Activation Status in Sepsis

Reduced miR-26b Expression in Megakaryocytes and Platelets Contributes to Elevated Level of Platelet Activation Status in Sepsis

AGE IS ASSOCIATED WITH INCREASED EXPRESSION OF PATTERN RECOGNITION RECEPTOR GENES ANDACE2, THE RECEPTOR FOR SARS-COV-2: IMPLICATIONS FOR THE EPIDEMIOLOGY OF COVID-19 DISEASE

Porphyromonas gingivalis lipopolysaccharide activates platelet Cdc42 and promotes platelet spreading and thrombosis

Contact Info

Product

Resources

About