RIPK3-Mediated Necroptosis Regulates Cardiac Allograft Rejection.
Bibliographic record
Abstract
Previous studies have shown that Tumour Necrosis Factor Alpha (TNFα) contributes to cell death by activating apoptotic and newly identified Receptor Interacting Protein Kinase 1 and 3 (RIPK1/RIPK3) mediated necroptotic death pathways. These variations in cell death may be important for graft survival as necroptosis can lead to the release of chemotactic and activating danger molecules which have been shown to activate host immune cells. This pathway has yet to be studied in transplantation. We isolated and treated microvascular endothelial cells (MVECs) from C57BL/6 hearts with TNFα in the presence and absence of RIPK1 inhibitor, necrostatin-1 (nec-1), and pan-caspase inhibitor, zVAD-fmk to inhibit and induce necroptosis, respectively. Release of pro-inflammatory danger molecule HMGB1 was also measured in the supernatant of cells following treatment. In vivo heterotopic heart transplantation was also performed using wildtype C57BL/6 or C57BL/6-RIPK3-/-donors into fully MHC mismatched BALB/c mice following short term sirolimus treatment. Graft survival, viability and danger molecule release were determined at several timepoints. Our data shows that sirolimus treatment (9 days) markedly prolongs cardiac allograft survival of RIPK3-/- donor grafts compared with wildtype donor heart grafts into Balb/c recipients (95 + 5.8 vs 24 + 2.6 days p<0.001). In vitro, MVEC cell death is reduced by the RIPK1/RIPK3 inhibiting small molecule nec-1 in the presence of zVAD-fmk following TNFα treatment (25.9 + 2.73% vs 15.6 + 2%, PI positive at 48 hours, n=3, p<0.05). As well, necrosis and release of the pro-inflammatory danger molecule HMGB1 are attenuated in vivo in RIPK3 null heart allografts and in vitro with VEC after RIPK1/RIPK3 inhibition. Finally, quantitative blinded scoring of graft infiltration, necrotic cell death and endothelial damage were attenuated in RIP3 null hearts compared with wildtype allografts. These data suggest that RIPK1/RIPK3 contributes to inflammatory injury in cardiac allografts through MVEC necroptotic death and the release of danger molecules. The ability of immunosuppression to provide rejection protection or permit tolerance is influenced by the level of cell death and inflammation. We suggest that targeting RIPK1 and/or RIPK3 may be an important therapeutic strategy in solid organ transplantation.
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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".