ATP citrate lyase (ACLY) regulates pro-inflammatory phenotypes in regulatory T cells in response to oxidized phospholipids 3848
Bibliographic record
Abstract
Abstract Description Regulatory T cells (Tregs) protect against atherosclerosis but lose stability and function as the disease progresses. Our lab has recently identified that the oxidized phospholipid oxPAPC (oxidized 1-palmitoyl-2- arachidonoyl-sn-glycero-3-phosphocholine), enriched in atherosclerosis, induces a Th1-like, T-bet+ IFNγ+ phenotype during inducible Treg differentiation. These cells have reduced suppressive capacity in vitro and are less protective against atherosclerosis in vivo. However, the mechanism of oxPAPC-induced Treg dysfunction remains unknown. We sought to elucidate this mechanism and show that the oxPAPC-induced Th1-like phenotype depends on ATP citrate lyase (ACLY), which regulates the conversion of citrate to acetyl-CoA, a metabolite with important roles in the epigenetic regulation of IFNγ production. We found that supplementing cultures with exogenous acetate, which increases acetyl-CoA levels in an ACLY-independent manner, restores the Th1-like phenotype in Acly deficient cells differentiated with oxPAPC. This indicates ACLY may act as a link between oxPAPC and pro-inflammatory cytokine expression via acetyl-CoA regulation. A role for ACLY in murine atherosclerosis was examined using mice with T-cell specific ACLY knockout. CD4Cre+Aclyfl/fl mice had reductions in T-bet+ Tregs and increased plaque stability compared to CD4Cre-Aclyfl/fl mice, indicating a pro-atherogenic role for T-cell ACLY. Overall, our findings support a role for T-cell ACLY in atherosclerosis. Funding Sources Supported by T32AI138932; NIAID R01AI153167; NIH R21AI176219; VA Merit Grant I01BX002968 Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".