Abstract 372: CD36 Signaling Regulates Autophagy to Limit Macrophage Cholesterol Accumulation
Bibliographic record
Abstract
Autophagy regulates cholesterol mobilization from lipid droplets, a rate-limiting step in macrophage reverse cholesterol transport. Here we investigated the molecular mechanisms of autophagy activation in macrophage foam cells and atherosclerotic plaque. Immunohistochemical staining of human atherosclerotic lesions for LC3 revealed elevated levels of this autophagy marker, particularly in macrophages located in the rupture-prone ‘shoulder region’ of the lesions. This suggests a ‘frustrated autophagy’ in these macrophages, which play important roles in the transition of plaques to a vulnerable state. Notably, we find that macrophages faced with prolonged lipid challenge in vitro exhibit a progressive defect in autophagic flux over time. Pharmacologic stimulation of autophagy in lipid-loaded macrophages enhances cholesterol efflux, suggesting that increasing arterial macrophage autophagy may be anti-atherogenic. However, the molecular mechanisms by which autophagy is stimulated in macrophage foam cells are unclear. Autophagy is rapidly activated in macrophages exposed to oxLDL. Given the role of scavenger receptors in the internalization and signaling response to oxLDL, we investigated whether autophagy activation in foam cells requires CD36. Using Cd36-/- macrophages, we find that oxLDL-induced autophagy is severely impaired compared to WT. Interestingly, preventing dynamin-dependent oxLDL uptake by CD36 does not alter oxLDL-induced autophagy, suggesting that CD36-signaling is sufficient to trigger autophagic activation. Previous studies have shown that CD36 mediates autonomous signaling via Src and MAP kinases, or pairs with Toll-like receptors, including TLR4, to induce the signaling response to oxLDL. Using macrophages from knockout mice, we show that oxLDL-triggered autophagy is intact in the absence of TLR4 or its adaptor MyD88. However, selective inhibition of Src kinases or the MAP kinases Erk and Jnk abolishes induction of LC3 in response to oxLDL. Accordingly, we observe a marked reduction in autophagy levels in plaque macrophages from Apoe-/-Cd36-/- mice on western diet. Together, our data indicate a role for CD36 signaling in limiting cholesterol accumulation in plaque macrophages via induction of autophagy.
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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) | 0.007 | 0.003 |
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".