Induction of the unfolded protein response after monocyte to macrophage differentiation augments cell survival in early atherosclerotic lesions
Bibliographic record
Abstract
ABSTRACT Endoplasmic reticulum (ER) stress causes macrophage cell death within advanced atherosclerotic lesions, thereby contributing to necrotic core formation and increasing the risk of atherothrombotic disease. However’ unlike in advanced lesions’ the appearance of dead/apoptotic macrophages in early lesions is less prominent. Given that activation of the unfolded protein response (UPR) is detected in early lesion‐resident macrophages and can enhance cell survival against ER stress’ we investigated whether UPR activation occurs after monocyte to macrophage differentiation and confers a cytoprotective advantage to the macrophage. Human peripheral blood monocytes were treated with monocyte colony‐stimulating factor to induce macrophage differentiation’ as assessed by changes in ultrastructure and scavenger receptor expression. UPR markers, including GRP78, GRP94, and spliced XBP‐1, were induced after macrophage differentiation and occurred after a significant increase in de novo protein synthesis. UPR activation after differentiation reduced macrophage cell death by ER stress‐inducing agents. Further, GRP78 overexpression in macrophages was sufficient to reduce ER stress‐induced cell death. Consistent with these in vitro findings, UPR activation was observed in viable lesion‐resident macrophages from human carotid arteries and from the aortas of apoE _/_ mice. However, no evidence of apoptosis was observed in early lesion‐resident macrophages from the aortas of apoE _/_ mice. Thus, our findings that UPR activation occurs during macrophage differentiation and is cyto‐protective against ER stress‐inducing agents suggest an important cellular mechanism for macrophage survival within early atherosclerotic lesions.—Dickhout, J. G., Lhotak, S., Hilditch, B. A., Basseri, S., Colgan, S. M., Lynn, E. G., Carlisle, R. E., Zhou, J., Sood, S. K., Ingram, A. J., Austin, R. C. Induction of the unfolded protein response after monocyte to macrophage differentiation augments cell survival in early atherosclerotic lesions. FASEB J. 25, 576–589 (2011). www.fasebj.org
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 teacher head, 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".