TLR3 Activation Is Involved in Venous Thrombosis Development
Bibliographic record
Abstract
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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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".