Reverse Transendothelial Migration of Intimal CD11c+ Dendritic Cells: Role in Intracellular Pathogen Removal and Effect on Atherosclerotic Lesions.
Bibliographic record
Abstract
Dendritic cells are antigen presenting cells that play a key role in the initiation of the adaptive immune response and in chronic inflammatory diseases such as atherosclerosis. Resident intimal CD11c+ cells are abundant in the normal arterial intima of mice, in regions predisposed to atherosclerosis. Upon induction of hypercholesterolemia, these cells engulf lipids and become the first foam cells in nascent lesions. However, their function in the normal aorta remains poorly understood. The purpose of this study is to show that their function is to protect the arterial intima against Chlamydia (C.) muridarum infection, and potentially against other intracellular and extracellular bacteria. This protection is achieved when intimal CD11c+ cells undergo reverse transendothelial migration (RTM) through the endothelium into the arterial circulation to remove the pathogen from the vessel wall. Systemic pathogens and stimulation of pattern recognition receptors trigger two waves of RTM of intimal CD11c+ cells, each was followed by recovery through proliferation of the remaining cells. Both waves of RTM were dependent on up-regulated expression of CCR7 and its ligand CCL19 by intimal CD11c+ cells. C. muridarum enters the arterial intima when infected circulating monocytes are recruited. The second wave of RTM removes the pathogen from the vessel wall. Inhibition of RTM (e.g. in Ccr7-/- mice) results in accumulation of C. muridarum in the vessel wall, which induces a local inflammatory response, that could be harmful to the arteria intima. Hypercholesterolemia and lipid loading of intimal CD11c+ cells by feeding Ldlr--/- mice high fat diet for one week results in inhibition of RTM of CD11c+ foam cells. Lipid loading did not affect CCR7 or CCL19 induction in intimal cells and incubation with CCL19 did not rescue RTM in atherosclerotic lesions. Studies in Asc-/- and Casp1-/- mice that are deficient in the production of cleaved IL-1ď ˘, as well as antibody blockade and rescue experiments revealed that RTM is dependent on IL-1ď ˘ production from the arterial endothelial cells. In addition, experiments with Il-1r1-/- mice suggest that RTM is dependent on receptor expression by the endothelial cells. Future studies will continue to investigate other factors and mechanisms that might play a role in RTM of intimal CD11c+ cells, and explore how they can be used to induce RTM in atherosclerotic lesions as a potential preventative therapy to reduce atherosclerotic plaque burden.
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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 | 0.000 |
| 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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
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".