The Role of Sphingosine-1-Phosphate in the Reverse Transendothelial Migration of Aortic Resident Intimal Myeloid Cells
Bibliographic record
Abstract
A population of myeloid cells (MCs) resides in the aortic intima at regions predisposed to atherosclerosis. In Ldlr-/- mice, these cells have been shown to take up lipid and become the first foam cells in nascent atherosclerotic lesions. We recently showed that reverse transendothelial migration (RTM) of intimal MCs into arterial blood is a protective response, clearing intracellular pathogens from the artery. RTM is triggered by systemic stimulation of cytokine and toll-like receptors (TLRs), e.g., TLR4 by lipopolysaccharide (LPS), and is inhibited under conditions of hypercholesterolemia. In this dissertation, we further refine the kinetics of LPS-induced RTM, showing that the abundance of intimal CD11c+ MCs is reduced as soon as 4-6 hours post-stimulation, as enumerated by en face immunoconfocal microscopy. Since sphingosine-1-phosphate (S1P) signaling via S1P receptors (S1PRs) is required for immune cell trafficking in lymphoid tissues, we hypothesize that S1P signaling is also required for RTM of intimal MCs following systemic stimulation of TLRs. In wildtype C57BL/6 mice, LPS induced the intimal expression of S1pr1, S1pr3, and sphingosine kinase 1 (Sphk1, one of two kinases responsible for S1P production). FTY720, a broad-spectrum S1PR modulator, blocked LPS-induced RTM. S1PR1 and S1PR3 modulators blocked RTM in a partial and additive manner. Cre-mediated deletion of S1PR1 in MCs blocked LPS-induced RTM, suggesting that myeloid-specific S1PR1 signaling is implicated in the migratory process. Furthermore, global loss or hematopoietic deficiency of SPHK1 reduced the level of S1P in the blood plasma and the abundance of CD11c+ MCs in the aortic intima, suggesting a role for S1P in the homeostatic maintenance of aortic MCs. Additionally, LPS-induced RTM occurred in mice with non-hematopoietic SPHK1 deficiency but not in mice with hematopoietic SPHK1 deficiency. Thus, functional and expression studies support a role for S1P signaling in both the maintenance of resident intimal MCs and LPS-induced RTM. Future work will investigate if S1P signaling is linked to intimal inflammatory signaling to regulate RTM, the factors that govern whether a subset of MCs preferentially undergoes RTM, and how hypercholesterolemia modulates molecular mechanisms that regulate RTM.
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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) | 0.000 | 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".