Abstract 550: Hypercholesterolemia Inhibits LPS-Induced CCR7-Dependent Reverse Transmigration of Arterial Intimal Dendritic Cells.
Bibliographic record
Abstract
Dendritic cells (DCs) play a key role in chronic inflammatory diseases such as atherosclerosis. Myeloid cells with features of DCs are abundant in the normal arterial intima of mice, in regions that are predisposed to atherosclerosis. Upon induction of hypercholesterolemia, these intimal DCs rapidly engulf lipids and transform into the initial foam cells of nascent atherosclerotic lesions. The function of intimal DCs in normal mice remains unknown. We observed that systemic stimulation of toll-like receptors (TLRs), specifically TLR4 by LPS and TLR3 by Poly(I:C), induced a rapid reduction in the number of DCs in the normal aortic intima. Absence of TUNNEL staining and use of CD11c-hBcl2 transgenic mice suggested that apoptosis did not account for the loss of intimal DCs. Immuno-gold staining for CD11c coupled with scanning electron microscopy of the aortic surface and ex vivo experiments determined that reverse transmigration (RTM) through the intact endothelial monolayer accounts for LPS-induced reduction of intimal DCs. Intimal DC loss was blocked by pretreatment of wild type mice with pertussis toxin or function-blocking anti-CCL19 antibody, and did not occur in CCR7-/- and Plt (CCL19-/- and CCL21-/-) mice. Assessment of CCR7, CCL19, and CCL21 mRNA expression and reciprocal bone marrow transplantation between CCR7-/- or Plt and wild type mice confirmed that RTM is dependent on CCR7 and CCL19 expression by intimal DCs. Feeding LDLR-/- mice a cholesterol rich diet (CRD) for just one week induced foam cell formation and inhibited LPS-induced RTM; however, CCR7 and CCL19 mRNA induction by LPS was not inhibited. These findings suggest that in the normal mouse aorta, in response to inflammatory stimuli, RTM of RIDCs is dependent on CCR7 signaling; whereas in the setting of hypercholesterolemia, CCR7 signaling is altered in lipid-loaded intimal DCs, which inhibits their RTM. Future experiments will investigate the possibility to overcome this inhibition, so that lipid can be removed from the artery wall by exiting lipid-loaded RIDCs.
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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 | 0.000 |
| 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 | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 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".