Abstract Th0041: Endothelial Cell Activation Impairs Macrophage Efferocytosis and Promotes Inflammation.
Bibliographic record
Abstract
Background: Atherosclerotic cardiovascular disease is characterized, in part, by endothelial dysfunction and impaired efferocytosis (clearing of dead cells). Endothelial cells (ECs) are poised to regulate efferocytosis within atherogenic vessels due to their strategic location, ability to respond to insults, and release of soluble mediators. The role of EC-macrophage communication in efferocytosis regulation and disease progression has yet to be fully understood. We hypothesize that ECs, in response to atheroprone stimuli, regulate macrophage efferocytosis through extracellular vesicle (EV) mediated cell-cell communication. Methods: Human Umbilical Vein Endothelial Cells (HUVECs) were activated with TNFα or left untreated (quiescent) and cocultured with THP-1 macrophages (MΦ) using transwells for 24h. RT-PCR was employed to measure the abundance of inflammatory and efferocytosis-related transcripts (e.g. ADAM17 , SIRPα , MerTK , and LRP-1 ) in cocultured THP-1 MΦ. An in vitro efferocytosis assay was performed using the cocultured THP-1 MΦ, where THP-1 MΦ were incubated with pHrodo-stained apoptotic cells at a 3:1 ratio for 2h; efferocytosis capacity was measured using confocal microscopy. EVs were isolated from the secretome of quiescent and TNFα-stimulated ECs using ultracentrifugation and characterized per MISEV2023 guidelines. EC-derived EVs were added to THP-1 MΦ, at a physiological concentration, for downstream efferocytosis assay and transcriptomic analysis. Results: THP-1 MΦ cocultured with activated ECs showed an increase in inflammatory markers and ADAM17 , while decreasing MerTK and LRP-1 , compared to naïve THP-1 MΦ (n=6, p<0.05). Efferocytic capacity was reduced in these MΦ (n=5, p≤0.0001) compared to naïve and THP-1 MΦ coculture with quiescent ECs. Activated ECs released more EVs compared to quiescent ECs (n=5, p=0.0063). THP-1 MΦ treated with activated EC-EVs showed a downregulation in efferocytic capacity (n=3, p<0.05), compared to naïve, activated EV-depleted secretome, and quiescent EC-EVs treatment. THP-1 MΦ treated with activated EC-EVs showed an upregulation in SIRPα and downregulation in MerTK and LRP-1 , compared to quiescent EC-EV treated MΦ (n=6, p<0.05). Conclusion: Our data reveal a critical role of activated EC-EVs in impairing macrophage efferocytosis and promoting a proinflammatory phenotype. Understanding EC-EV-mediated regulation of efferocytosis would provide insight into novel therapeutic strategies for atherosclerosis treatment.
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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) | 0.001 | 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 | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.009 | 0.002 |
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".