TLR3 Activation Is Involved in Venous Thrombosis Development
Notice bibliographique
Résumé
Abstract Abstract 3309 Venous thromboembolism (VTE) afflicts 117 people per 100,000 each year and is an important cause of morbidity and mortality. The pathophysiology of VTE is now better understood from experimental studies. Leukocytes, chemokines, and proinflammatory cytokines are involved in VTE resolution and vein wall healing. This process resembles sterile wound healing with distinct phases of polymorphonucleic neutrophil and monocyte influx followed by fibrosis. Inflammation is emerging as a central mechanism in both the genesis and resolution of VTE. Recently, the role of toll-like receptor (TLR) signaling in modulating sterile inflammation has become better defined in experimental injury models. TLR3 senses dsRNA, a by-product of viral replication, in the endosome. In addition, TLR3 has been increasingly linked to tissue damage. Endogenous RNA released by damaged tissue or necrotic cells is able to induce TLR3 expression and signaling. Thus, we hypothesize that TLR3 might be involved in the inflammatory development of VTE. Intravenous injection of polyinosine polycytidylic acid (polyI:C), a synthetic double-stranded RNA analog, increases the size of thrombi after FeCl3-induced inferior vena cava injury (IVC) compared to mice treated with vehicle control (p<0.05). In TLR3 deficient (TLR3−/−) mice, polyI:C did not induce a further increase in thrombus size compared to vehicle control. Recently, neutrophils have been shown to initiate and propagate venous thrombosis. PolyI:C injection was associated with an increased of neutrophil infiltration in the thrombus in WT but not in TLR3−/− mice (p<0.05). We found that polyI:C injection was associated with increased neutrophil activation. In the thrombus of WT mice, immunofluorescence staining for myeloperoxidase and citrulinated H3, markers for neutrophils activation, were increased by polyI:C. Interestingly, in TLR3−/− mice, no increase of these markers was found after polyI:C injection as compared to vehicle control. In vitro incubation of endothelial cells with polyI:C induces production of pro-inflammatory cytokines IL-8 and CCL5 involved in the recruitment of neutrophils as demonstrated by a cytokine array. We found that mRNA expression of TLR3, IL-8 and CCL5 were dramatically increased with polyI:C. When endothelial cells were transfected with siRNA for TLR3, mRNA expression of TLR3, IL-8 and CCL5 was blunted in response to polyI:C. These results suggest that release of IL-8 and CCL5 from endothelial cells after TLR3 activation are involved in neutrophil recruitment. Taken together, these results strongly suggest that TLR3 stimulation after endothelial cell injury participate in thrombus formation by inducing a pro-inflammatory response leading to the recruitment and activation of neutrophils. Disclosures: No relevant conflicts of interest to declare.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,001 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,006 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».