Abstract 49: The Neuroimmune Guidance Molecule Semaphorin 3e Is Expressed in Macrophages of Advanced Atherosclerotic Plaques and Induces Macrophage Chemostasis
Bibliographic record
Abstract
Objective: The persistence of myeloid-derived cells in the artery wall is a characteristic of advanced atherosclerotic plaques. However, the mechanisms by which these cells are retained in plaques are poorly understood. Recently, we reported the involvement of Netrin-1, a neuronal guidance molecule, in promoting chronic inflammation in atherosclerosis by retaining macrophages in plaque. Semaphorins, another class of neuronal guidance molecules, play a critical role in vascular patterning and development, yet little is known about their role in atherosclerosis. The present study evaluates the expression of Sema3E in the setting of atherosclerosis and its contribution to macrophage accumulation in the atherosclerotic plaque. Methods and Results: Immunofluorescence staining of aortic root plaques from ApoE -/- mice fed a western diet showed abundant expression of Sema3E, as well as its ligand binding receptor PlexinD1, in macrophage foam cells. In vitro, incubation of bone marrow derived macrophages with physiological drivers of plaque inflammation, OxLDL and hypoxia, induced a 3 and 6 fold up-regulation of Sema3E mRNA levels respectively. In addition, Sema3E was also found to be upregulated 4-fold in inflammatory M1 macrophages compared to their more reparative counterpart, M2 macrophages. To understand how this guidance molecule affects macrophage behavior, we treated macrophages with recombinant (r)Sema3E in the presence/absence of CCL19, a chemokine implicated in the egress of macrophages from atherosclerotic plaques. (r)Sema3E blocked actin polymerization and macrophage migration stimulated by CCL19, suggesting that it may act to immobilize these cells in the plaque. Notably, in two different mouse models of atherosclerosis regression, Sema3E mRNA was highly downregulated in macrophages isolated from regressing plaques compared to progressing plaques. Furthermore, the decrease in Sema3E mRNA and protein in regressing plaques coincided with a reduction in plaque macrophage content and an enrichment in markers of M2 macrophages. Conclusion: Together, these findings suggest a role for Sema3E in promoting macrophage retention in atherosclerosis and highlight the emerging role for negative regulators of leukocyte migration in promoting chronic inflammation.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 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".